hrsACE2 intravenous infusion twice daily. Surprisingly after the first injection the patient became afebrile, the biological investigation indicated a marked reduction of Ang II, an increase of sACE2 in plasma, and her clinical condition improved gradually (Zoufaly et al., 2020). A large phase II clinical trial has been initiated by the Austrian pharmaceutical company APEIRON to treat COVID-19 patients with APN01-rhACE2. More recently, hrsACE2, in combination with sub-toxic remdesivir, was found to reduce viral load by 60% in a model of SARS-CoV-2 infected kidney organoids (Monteil et al., 2021).

Given such encouraging results, it seemed important to design molecules with improved activity against SARS-CoV-2 (Maiti, 2021; Figure 10B) A fusion molecule consisting of murine rACE2 with a Fc fragment (rACE2-Fc), demonstrated a long-lasting ability to protect organs in mice models of Ang II-dependent hypertension (Liu et al., 2018). It was also reported that *Lactobacillus paracasi* probiotic expressing a hrACE2 extracellular domain in fusion with the nontoxic subunit B of cholera toxin, resulted in increased ACE2 activities in serum of mice treated with this compound (Verma et al., 2019). Another molecule, rACE2 extracellular domain fused to the FC region of the IgG1, has been shown to neutralize viruses pseudotyped with SARS-CoV-2 spike proteins in vitro (Lei et al., 2020). A new set of molecules named “ACE2 receptor trap” that contain the extracellular domain residues 18–614 (including the SARS-CoV-2 RBD), and collectrin domain of ACE2 fused to human IgG1 Fc fragment for increased stabilization and avidity, were designed (Glasgow et al., 2020). *In silico*, ACE2 variants Lys<sub>26</sub>Arg and Thr<sub>92</sub>Ile were predicted to have increased affinity for the viral S protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 Lys<sub>26</sub>Arg and Thr<sub>92</sub>Ile were more effective in blocking the entry of the SARS-CoV-2S protein pseudotyped virus (Suryamohan et al., 2021). Another type of therapeutic molecules containg the hrsACE2 fused with a 5 kD albumin binding domain and bridged *via* a dimerization hinge-like peptide motif (termed ACE2 1-618-DDC-ABD) was first tested in an animal model prevented mortality in the treated group while untreated animals became severely ill and were found to have extensive pulmonary hemorrhage and mononuclear infiltrates (Hassler et al., 2021). The very rapid accumulation of three-dimensional structural data is likely to greatly accelerate the development of molecules aimed at treating COVID-19 patients (Sorokina et al., 2020).

Discussion

For virologists, ACE2 is the receptor for Sarbecoviruses. But to see ACE2 as a simple receptor necessary to initiate the replication cycle of the virus would be to ignore the essential role of ACE2 in the pathophysiology of COVID-19. ACE2 was not maintained during species evolution to wait for an unlikely meeting with a spike of Sarbecovirus. The regulatory function of the RAS pathway naturally devolved to ACE2 is the key element

to be considered. The imbalance of the RAS pathway followed by the uncontrolled elevation of Ang II levels in SARS-CoV-2 infected patients and signaling through AT1R is the triggering event that can lead to severe forms of COVID-19. Thereby, COVID-19 is primarily a vascular rather than a respiratory disease and Ang II/AT1R blockade might attenuate progression to COVID-19.

The global COVID-19 Host Genetics Initiative (HGI) was set up to bring together international experts in human genetics and epidemiology to explore the genetic determinants of COVID-19 susceptibility, who have shed light on several host factors including ACE2, ACE, TMPRSS2, several chemokine receptors, the IL-6 receptor, IFN, and HLA, which are likely at the forefront of parameters affecting the disease severity (Correale et al., 2020; Ellinghaus et al., 2020; Initiative, 2020; Karaderi et al., 2020; Lorente et al., 2020; Nguyen et al., 2020; Strafella et al., 2020; Zhang Q. et al., 2020; Fricke-Galindo, 2021; Goujon et al., 2021; Martin-Sanchos et al., 2021; Pairo-Castineira et al., 2021). The list of genes possibly involved in the severity of COVID-19 continues to grow and indicates that the predisposition to severe COVID-19 is multifactorial. Understanding these pathways may help identifying targets for COVID-19 therapy and prophylaxis. Although the implication of a multiplicity of genes in the severity of COVID-19 is oubvious when considering the heterogenity in patient's cases, we consider members of RAS as the main actors of the pathophysiological process. Besides ACE2 and Ang II, RAS can also be regulated by insertion/deletion (I/D) polymorphism of the ACE gene increasing the risk of severe forms of COVID-19 (Marshall et al., 2002; Harrap et al., 2003; Sayed-Tabatabaei et al., 2006; Gupta et al., 2009; Yamamoto et al., 2021). Association between the I/D polymorphism and blood pressure status has been reported (Jeunemaitre et al., 1992; Schmidt et al., 1993; Duru et al., 1994; Kario et al., 1999; Giner et al., 2000; Martinez et al., 2000; Agachan et al., 2003). Infusion of Ang I into normosensitive men was followed by higher venous levels of Ang II and increase in blood pressure in D/D carriers compared with I/I carriers (Ueda et al., 1995). Moreover, it has been reported that higher plasma IL-6 levels can be detected in ST segment elevation myocardial infarction patients, when the D allele is present (Dai et al., 2019). The possible association between the ACE genotype and the severity of COVID-19 should be further explored (Celik et al., 2021; Verma et al., 2021). One report indicates that the prevalence of D/D polymorphism is higher in COVID-19 patients with pulmonary embolism (PE) than patients without PE (Calabrese et al., 2021).

Our review highlights that the most important factors associated with severe COVID-19 outcome are related to the RAS and the regulation of blood pressure and coagulation. By focusing our attention to ACE2, we have come to the conclusion that this molecule may potentially play contrasting roles at different stages of the disease, with its ability to enable viral entry into the cell at early stages of infection thereby increasing disease susceptibility
hrsACE2 intravenous infusion twice daily. Surprisingly after the first injection the patient became afebrile, the biological investigation indicated a marked reduction of Ang II, an increase of sACE2 in plasma, and her clinical condition improved gradually (Zoufaly et al., 2020). A large phase II clinical trial has been initiated by the Austrian pharmaceutical company APEIRON to treat COVID-19 patients with APN01-rhACE2. More recently, hrsACE2, in combination with sub-toxic remdesivir, was found to reduce viral load by 60% in a model of SARS-CoV-2 infected kidney organoids (Monteil et al., 2021).

Given such encouraging results, it seemed important to design molecules with improved activity against SARS-CoV-2 (Maiti, 2021; Figure 10B) A fusion molecule consisting of murine rACE2 with a Fc fragment (rACE2-Fc), demonstrated a long-lasting ability to protect organs in mice models of Ang II-dependent hypertension (Liu et al., 2018). It was also reported that *Lactobacillus paracasi* probiotic expressing a hrACE2 extracellular domain in fusion with the nontoxic subunit B of cholera toxin, resulted in increased ACE2 activities in serum of mice treated with this compound (Verma et al., 2019). Another molecule, rACE2 extracellular domain fused to the FC region of the IgG1, has been shown to neutralize viruses pseudotyped with SARS-CoV-2 spike proteins in vitro (Lei et al., 2020). A new set of molecules named “ACE2 receptor trap” that contain the extracellular domain residues 18–614 (including the SARS-CoV-2 RBD), and collectrin domain of ACE2 fused to human IgG1 Fc fragment for increased stabilization and avidity, were designed (Glasgow et al., 2020). *In silico*, ACE2 variants Lys<sub>26</sub>Arg and Thr<sub>92</sub>Ile were predicted to have increased affinity for the viral S protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 Lys<sub>26</sub>Arg and Thr<sub>92</sub>Ile were more effective in blocking the entry of the SARS-CoV-2S protein pseudotyped virus (Suryamohan et al., 2021). Another type of therapeutic molecules containg the hrsACE2 fused with a 5 kD albumin binding domain and bridged *via* a dimerization hinge-like peptide motif (termed ACE2 1-618-DDC-ABD) was first tested in an animal model prevented mortality in the treated group while untreated animals became severely ill and were found to have extensive pulmonary hemorrhage and mononuclear infiltrates (Hassler et al., 2021). The very rapid accumulation of three-dimensional structural data is likely to greatly accelerate the development of molecules aimed at treating COVID-19 patients (Sorokina et al., 2020).

Discussion

For virologists, ACE2 is the receptor for Sarbecoviruses. But to see ACE2 as a simple receptor necessary to initiate the replication cycle of the virus would be to ignore the essential role of ACE2 in the pathophysiology of COVID-19. ACE2 was not maintained during species evolution to wait for an unlikely meeting with a spike of Sarbecovirus. The regulatory function of the RAS pathway naturally devolved to ACE2 is the key element

to be considered. The imbalance of the RAS pathway followed by the uncontrolled elevation of Ang II levels in SARS-CoV-2 infected patients and signaling through AT1R is the triggering event that can lead to severe forms of COVID-19. Thereby, COVID-19 is primarily a vascular rather than a respiratory disease and Ang II/AT1R blockade might attenuate progression to COVID-19.

The global COVID-19 Host Genetics Initiative (HGI) was set up to bring together international experts in human genetics and epidemiology to explore the genetic determinants of COVID-19 susceptibility, who have shed light on several host factors including ACE2, ACE, TMPRSS2, several chemokine receptors, the IL-6 receptor, IFN, and HLA, which are likely at the forefront of parameters affecting the disease severity (Correale et al., 2020; Ellinghaus et al., 2020; Initiative, 2020; Karaderi et al., 2020; Lorente et al., 2020; Nguyen et al., 2020; Strafella et al., 2020; Zhang Q. et al., 2020; Fricke-Galindo, 2021; Goujon et al., 2021; Martin-Sanchos et al., 2021; Pairo-Castineira et al., 2021). The list of genes possibly involved in the severity of COVID-19 continues to grow and indicates that the predisposition to severe COVID-19 is multifactorial. Understanding these pathways may help identifying targets for COVID-19 therapy and prophylaxis. Although the implication of a multiplicity of genes in the severity of COVID-19 is oubvious when considering the heterogenity in patient's cases, we consider members of RAS as the main actors of the pathophysiological process. Besides ACE2 and Ang II, RAS can also be regulated by insertion/deletion (I/D) polymorphism of the ACE gene increasing the risk of severe forms of COVID-19 (Marshall et al., 2002; Harrap et al., 2003; Sayed-Tabatabaei et al., 2006; Gupta et al., 2009; Yamamoto et al., 2021). Association between the I/D polymorphism and blood pressure status has been reported (Jeunemaitre et al., 1992; Schmidt et al., 1993; Duru et al., 1994; Kario et al., 1999; Giner et al., 2000; Martinez et al., 2000; Agachan et al., 2003). Infusion of Ang I into normosensitive men was followed by higher venous levels of Ang II and increase in blood pressure in D/D carriers compared with I/I carriers (Ueda et al., 1995). Moreover, it has been reported that higher plasma IL-6 levels can be detected in ST segment elevation myocardial infarction patients, when the D allele is present (Dai et al., 2019). The possible association between the ACE genotype and the severity of COVID-19 should be further explored (Celik et al., 2021; Verma et al., 2021). One report indicates that the prevalence of D/D polymorphism is higher in COVID-19 patients with pulmonary embolism (PE) than patients without PE (Calabrese et al., 2021).

Our review highlights that the most important factors associated with severe COVID-19 outcome are related to the RAS and the regulation of blood pressure and coagulation. By focusing our attention to ACE2, we have come to the conclusion that this molecule may potentially play contrasting roles at different stages of the disease, with its ability to enable viral entry into the cell at early stages of infection thereby increasing disease susceptibility
and later by decreasing Ang II/AT1R signaling thereby reducing the severity of the disease. Revisiting the structure and function of this molecule highlights the crucial role of ACE2 in the pathophysiology of sarbecoviruses-induced diseases, particularly in the context of inflammation and thrombosis. A low expression of ACE2 in the respiratory tract (e.g., epithelial cells, arterial and venous endothelial cells present in abundance in the lungs, and arterial smooth muscles) is associated with increased circulating levels of Ang II. The interaction of Ang II with AT1R and activation of various AT1R-dependent signaling pathways induce ROS release from monocytes able to trigger DNA damages and apoptosis in neighboring T-cells leading to lymphopenia, and endothelial injury by inhibiting NO synthesis. It is associated with vasoconstriction, hypertension, vascular permeability, fluid extravasation, and accelerated thrombosis in arterioles by activating hemostasis and the complement system. This process is accompanied by a recruitment of neutrophils and macrophages to the affected tissues leading to the "cytokine storm" (e.g., IL-6, MIP2, TNFα, and IFN responses). Perivascular inflammation is composed mainly of lymphocytes, with thrombi in the branches of the pulmonary artery and focal areas of congestion in the alveolar septal capillaries, as well as septal capillary lesions with wall and luminal fibrin deposition. Taken as a whole, these observations lead us to assume that instead of considering COVID-19 as respiratory tract diseases, we should rather see this disease as a clinical picture of hypercoagulopathy, microvascular immunothrombosis, and hyperinflammation. The loss of ACE2 function after the binding of SARS-CoV-2 is driven by mACE2 receptor endocytosis, activation of proteolytic cleavage of mACE2 and ACE2 gene transcriptional downregulation. Accurate quantification of RAS biomarkers should be added to the collection of tools aimed at monitoring COVID-19 infection both at pre-clinical and clinical levels.

According to the literature and our own observations, ACE2 and Ang II are the most relevant host factors in later stages of the disease and ACE2 should be seen as an ally in the global fight against COVID-19 and should be considered when designing appropriated drugs for COVID-19 therapy. It now appears that we can see the direction in wich work to deal with this disease should head. It requires treatment consisting in maintaining the homeostasis of the RAS pathway by preventing the elevation of the circulating levels of Ang II through sufficient biodisponibility of ACE2 to hydrolyze Ang II (including the use of human recombinant soluble ACE2), by inhibiting the Ang II/AT1R axis using ARBs which decrease the surface expression of AT1R, and/or by using calcium channel blokers as an alternative to ACEi and ARBS.

## References

Abbasi, J. (2021). Choose ARBs over ACE inhibitors for first-line hypertension treatment, large new analysis suggests. JAMA 326, 1244-1245. doi: 10.1001/jama.2021.14017

## Author contributions

CD conceived the manuscript and wrote the first draft. LC-J participated in the correction of the manuscript. Both authors contributed to the article and approved the submitted version.

## Funding

This work was supported by the French Government under the "Investissements d'avenir" (Investments for the Future) program managed by the Agence Nationale de la Recherche (French ANR: National Agency for Research; reference: Méditerranée Infection 10-IAHU-03 to Professor Didier Raoult), and annual funds from Aix-Marseille university and IRD to the MEPHI research unit (Director: Professor Jean-Christophe Lagier). Other funding sources were limited to the salaries of the authors (Center National de la Recherche Scientifique for CAD, Assistance Publique Hôpitaux de Marseille for LCJ), with no other role or involvement.

## Acknowledgments

We thank JC Lagier and D. Raoult for stimulating discussions and their unwavering support. Figures were designed using the Servier Medical Art supply of images available under a Creative Commons CC BY 3.0 license.

## Conflict of interest

CD declares a link of interest with the Sanofi and Merck pharmaceutical companies.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

AbdAlla, S., Lother, H., and Quitterer, U. (2000). AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 407, 94-98. doi: 10.1038/35024095
and later by decreasing Ang II/AT1R signaling thereby reducing the severity of the disease. Revisiting the structure and function of this molecule highlights the crucial role of ACE2 in the pathophysiology of sarbecoviruses-induced diseases, particularly in the context of inflammation and thrombosis. A low expression of ACE2 in the respiratory tract (e.g., epithelial cells, arterial and venous endothelial cells present in abundance in the lungs, and arterial smooth muscles) is associated with increased circulating levels of Ang II. The interaction of Ang II with AT1R and activation of various AT1R-dependent signaling pathways induce ROS release from monocytes able to trigger DNA damages and apoptosis in neighboring T-cells leading to lymphopenia, and endothelial injury by inhibiting NO synthesis. It is associated with vasoconstriction, hypertension, vascular permeability, fluid extravasation, and accelerated thrombosis in arterioles by activating hemostasis and the complement system. This process is accompanied by a recruitment of neutrophils and macrophages to the affected tissues leading to the “cytokine storm” (e.g., IL-6, MIP2, TNFα, and IFN responses). Perivascular inflammation is composed mainly of lymphocytes, with thrombi in the branches of the pulmonary artery and focal areas of congestion in the alveolar septal capillaries, as well as septal capillary lesions with wall and luminal fibrin deposition. Taken as a whole, these observations lead us to assume that instead of considering COVID-19 as respiratory tract diseases, we should rather see this disease as a clinical picture of hypercoagulopathy, microvascular immunothrombosis, and hyperinflammation. The loss of ACE2 function after the binding of SARS-CoV-2 is driven by mACE2 receptor endocytosis, activation of proteolytic cleavage of mACE2 and ACE2 gene transcriptional downregulation. Accurate quantification of RAS biomarkers should be added to the collection of tools aimed at monitoring COVID-19 infection both at pre-clinical and clinical levels.

According to the literature and our own observations, ACE2 and Ang II are the most relevant host factors in later stages of the disease and ACE2 should be seen as an ally in the global fight against COVID-19 and should be considered when designing appropriated drugs for COVID-19 therapy. It now appears that we can see the direction in wich work to deal with this disease should head. It requires treatment consisting in maintaining the homeostasis of the RAS pathway by preventing the elevation of the circulating levels of Ang II through sufficient biodisponibility of ACE2 to hydrolyze Ang II (including the use of human recombinant soluble ACE2), by inhibiting the Ang II/AT1R axis using ARBs which decrease the surface expression of AT1R, and/or by using calcium channel blokers as an alternative to ACEi and ARBS.

## References

Abbasi, J. (2021). Choose ARBs over ACE inhibitors for first-line hypertension treatment, large new analysis suggests. JAMA 326, 1244-1245. doi: 10.1001/jama.2021.14017

## Author contributions

CD conceived the manuscript and wrote the first draft. LC-J participated in the correction of the manuscript. Both authors contributed to the article and approved the submitted version.

## Funding

This work was supported by the French Government under the "Investissements d'avenir" (Investments for the Future) program managed by the Agence Nationale de la Recherche (French ANR: National Agency for Research; reference: Méditerranée Infection 10-IAHU-03 to Professor Didier Raoult), and annual funds from Aix-Marseille university and IRD to the MEPHI research unit (Director: Professor Jean-Christophe Lagier). Other funding sources were limited to the salaries of the authors (Center National de la Recherche Scientifique for CAD, Assistance Publique Hôpitaux de Marseille for LCJ), with no other role or involvement.

## Acknowledgments

We thank JC Lagier and D. Raoult for stimulating discussions and their unwavering support. Figures were designed using the Servier Medical Art supply of images available under a Creative Commons CC BY 3.0 license.

## Conflict of interest

CD declares a link of interest with the Sanofi and Merck pharmaceutical companies.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Frutos, R., Yahi, N., Gavotte, L., Fantini, J., and Devaux, C. A. (2022). Role of spike compensatory mutations in the interspecies transmission of SARS-CoV-2. *One Health* 15:100429. doi: 10.1016/j. onehlt.2022.100429

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Furuhashi, M., Moniwa, N., Takizawa, H., Ura, N., and Shimamoto, K. (2020). Potential differential effects of renin-angiotensin system inhibitors on SARS-CoV-2 infection and lung injury in COVID-19. *Hypertens. Res.* 43, 837–840. doi: 10.1038/s41440-020-0478-1

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Gagiannis, D., Steinestel, J., Hackenbroch, C., Schreiner, B., Hannemann, M., Bloch, W., et al. (2020). Clinical, serological, and histopathological similarities between severe COVID-19 and acute exacerbation of connective tissue disease-associated interstitial lung disease (CTD-ILD). *Front. Immunol.* 11:587517. doi: 10.3389/fimmu.2020.587517

Gaidarov, I., Adams, J., Frazer, J., Anthony, T., Chen, X., Gatlin, J., et al. (2018). Angiotensin (1-7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor. *Cell. Signal.* 50, 9–24. doi: 10.1016/j. cellsig.2018.06.007

Gallucio, M., Pantanella, M., Gludice, D., Brescia, S., and Indiveri, C. (2020). Low temperature bacterial expression of the neutral amino acid transporters SLC1A5 (ASCT2), and SLC6A19 (B0AT1). *Mol. Biol. Rep.* 47, 7283–7289. doi: 10.1007/s11033-020-05717-8

Gando, S., and Wada, T. (2021). Thromboplasminflammation in COVID-19 coagulopathy: three viewpoints for diagnostic and therapeutic strategies. *Front. Immunol.* 12:649122. doi: 10.3389/fimmu.2021.649122

Gao, S., and Zhang, L. (2020). ACE2 partially dictates the host range and tropism of SARS-CoV-2. *Comput. Struct. Biotechnol.* J. 18, 4040–4047. doi: 10.1016/j. csbj.2020.11.032

Garcia-Escobar, A., Jimenez-Valero, S., Galeote, G., Jurado-Roman, A., Garcia-Rodriguez, J., and Moreno, R. (2021). The soluble catalytic ectodomain of ACE2 a biomarker of cardiac remodelling: new insights for heart failure and COVID19. *Heart Fail. Rev.* 26, 961–971. doi: 10.1007/s10741-020-10066-6

Garrido, A. M., and Griendling, K. K. (2009). NADPH oxidases and angiotensin II receptor signaling. *Mol. Cell. Endocrinol.* 302, 148–158. doi: 10.1016/j. mce.2008.11.003

Garvin, M. R., Alvarez, C., Miller, J. I., Prates, E. T., Walker, A. M., Amos, B. K., et al. (2020). A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. *elife* 9:e59177. doi: 10.7554/eLife.59177

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Han, H., Ma, Q., Li, C., Liu, R., Zhao, L., Wang, W., et al. (2020). Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. *Emerg. Microb. Infect.* 9, 1123–1130. doi: 10.1080/22221751.2020.1770129

Han, Y., Runge, M. S., and Brasier, A. R. (1999). Angiotensin II induces Interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kB transcription factors. *Circ. Res.* 84, 695–703. doi: 10.1161/01 RES.84.6.695

Harrap, S. B., Tzourio, C., Cambien, F., Poirier, O., Raoux, S., Chalmers, J., et al. (2003). The ACE gene I/D polymorphism is not associated with the blood pressure and cardiovascular benefits of ACE inhibition. *Hypertension* 42, 297–303. doi: 10.1161/01 HYP.0000088322.85804.96

Hartzallah, I., Debliquis, A., and Drenou, B. (2020). Lupus anticoagulant is frequent in patients with Covid-19. *J. Thromb. Haemost.* 18, 2064–2065. doi: 10.1111/jth.14867

Haschke, M., Schuster, M., Poglitsch, M., Loiner, H., Salzberg, M., Bruggisser, M., et al. (2013). Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. *Clin. Pharmacokinet.* 52, 783–792. doi: 10.1007/s40262-013-0072-7

Hashimoto, T., Perlot, T., Rehman, A., Trichereau, J., Ishiguro, H., Paolino, M., et al. (2012). ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. *Nature* 487, 477–481. doi: 10.1038/nature11228

Hassler, L., Wysocki, J., Gelarden, I., Tomatsidou, A., Gula, H., Nicoleascu, V., et al. (2021). A novel soluble ACE2 protein totally protects from lethal disease caused by SARS-CoV-2 infection. *bioRxiv* [Preprint] doi: 10.1101/2021.03.12.435191

He, M., He, X., Xie, Q., Chen, F., and He, S. (2006). Angiotensin II induces the expression of tissue factor and its mechanism in human monocytes. *Thromb. Res.* 117, 579–590. doi: 10.1016/j.thromres.2005.04.033

Heeneman, S., Haendeler, J., Saito, Y., Ishida, M., and Berk, B. C. (2000). Angiotensin II induces transactivation of two different populations of the platelet-derived growth factor beta receptor. Key role for the p66 adaptor protein Shc. *J. Biol. Chem.* 275, 15926–15932. doi: 10.1074/jbc.M909616199

Helms, J., Tacquard, C., Severac, F., Leonard-Lorant, I., Ohana, M., Delabranche, X., et al. (2020). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. *Intensive Care Med.* 46, 1089–1098. doi: 10.1007/s00134-020-06062-x

Hemnes, A. R., Rathinasabapathy, A., Austin, E. A., Brittain, E. L., Carrier, E. J., Chen, X., et al. (2018). A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. *Eur. Respir. J.* 51:1702638. doi: 10.1183/13993003.02638-2017

Hendren, N. S., Drazner, M. H., Bozkurt, B., and Cooper, L. T. (2020). Description and proposed management of the acute COVID-19 cardiovascular syndrome. *Circulation* 141, 1903–1914. doi: 10.1161/CIRCULATIONAHA.120.047349

Henzinger, H., Barth, D. A., Klec, C., and Pichler, M. (2020). Non-Coding RNAs and SARS-related coronaviruses. *Viruses* 12:1374. doi: 10.3390/v12121374

Hernández Prada, J. A., Ferreira, A. J., Katovich, M. J., Shenoy, V., Qi, Y., Santos, R. A., et al. (2008). Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. *Hypertension* 51, 1312–1317. doi: 10.1161/HYPERTENSIONAHA.107.108944

Heurich, A., Hofmann-Winkler, H., Gierer, S., Liepold, T., Jahn, O., and Pöhlmann, S. (2014). TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. *J. Virol.* 88, 1293–1307. doi: 10.1128/JVI.02202-13

Heyman, S. N., Kinaneh, S., and Abassi, Z. (2021). The duplicitous nature of ACE2 in COVID-19 disease. *EBioMed.* 67:103356. doi: 10.1016/j.ebiom.2021.103356

Hikmet, F., Méar, L., Edvinsson, A., Micke, P., Uhlén, M., and Lindskog, C. (2020). The protein expression profile of ACE2 in human tissues. *Mol. Syst. Biol.* 16:e9610. doi: 10.15252/msb.20209610

Hirano, T., and Murakami, M. (2020). COVID-19: a new virus, but a familiar receptor and cytokine release syndrome. *Immunity* 52, 731–733. doi: 10.1016/j.immuni.2020.04.003

Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. *Cells* 181, 271–280.e8. doi: 10.1016/j.cell.2020.02.052

Hofman, P., Copin, M. C., Tauziede-Espariat, A., Adle-Biassette, H., Fortarezza, F., Passeron, T., et al. (2021). Histopathological features due to the SARS-CoV-2 [in French]. *Ann. Pathol.* 41, 9–22. doi: 10.1016/j.annpat.2020.1.2009

Hofmann, H., Pyrc, K., van der Hoek, L., Geier, M., Berkhout, B., and Pöhlmann, S. (2005). Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. *Proc. Natl. Acad. Sci. U. S. A.* 102, 7988–7993. doi: 10.1073/pnas.0409465102

Horowitz, JE, Kosmicki, JA, Damask, A, Sharma, D, Roberts, GHL, Justice, AE, et al. Genome-wide analysis in 756, 646 individuals provides first evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease [Internet]. *medRxiv* [Preprint]. (2021). doi: 10.1101/2020.12.14.20248176

Hou, Y., Zhao, J., Martin, W., Kallianpur, A., Chung, M. K., Jehi, L., et al. (2020). New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. *BMC Med.* 18:216. doi: 10.1186/s12916-020-01673-z

Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. *Lancet* 395, 497–506. doi: 10.1016/S0140-6736(20)30183-5

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Krishnamurthy, S., Lockey, R. F., and Kolliputi, N. (2021). Soluble ACE2 as a potential therapy for COVID-19. *Am. J. Phys. Cell Physiol.* 320, C279–C281. doi: 10.1152/ajpcell.00478.2020

Ksiazek, T. G., Erdman, D., Goldsmith, C. S., Zaki, S. R., Peret, T., Emery, S., et al. (2003). A novel coronavirus associated with severe acute respiratory syndrome. *N. Engl. J. Med.* 348, 1953–1966. doi: 10.1056/NEJMoa030781

Kuan, T. C., Yang, T. H., Wen, C. H., Chen, M. Y., Lee, I. L., and Lin, C. S. (2011). Identifying the regulatory element for human angiotensin-converting enzyme 2 (ACE2) expression in human cardiofibroblasts. *Peptides* 32, 1832–1839. doi: 10.1016/j.peptides.2011.08.009

Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., et al. (2005). A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. *Nat. Med.* 11, 875–879. doi: 10.1038/nm1267

Kulemina, L. V., and Ostrov, D. A. (2011). Prediction of off-target effects on angiotensin-converting enzyme 2. *J. Biomol. Screen.* 16, 878–885. doi: 10.1177/1087057111413919

Kundura, L., Gimenez, S., Cezar, R., André, S., Younas, M., Lin, Y. L., et al. (2022). Angiotensin II induces reactive oxygen species, DNA damage, and T-cell apoptosis in severe COVID-19. *J. Allergy Clin. Immunol.* 150, 594–603.e2. doi: 10.1016/j.jaci.2022.06.020

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Lam, S. D., Bordin, N., Waman, V. P., Scholes, H. M., Ashford, P., Sen, N., et al. (2020). SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals. *Sci. Rep.* 10:16471. doi: 10.1038/s41598-020-71936-5

Lambert, D. W., Clarke, N. E., Hooper, N. M., and Turner, A. J. (2008). Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain. *FEBS Lett.* 582, 385–390. doi: 10.1016/j.feeslet.2007.11.085

Lambert, D. W., Yarski, M., and Warner, F. J. (2005). Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). *J. Biol. Chem.* 280, 30113–33019. doi: 10.1074/jbc.M505111200

Lamers, M. M., Beumer, J., van der Vaart, J., Knoops, K., Puschhof, J., Breugem, T. I., et al. (2020). SARS-CoV-2 productively infects human gut enterocytes. *Science* 369, 50–54. doi: 10.1126/science.abc1669

Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., et al. (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. *Nature* 581, 215–220. doi: 10.1038/s41586-020-2180-5

Lanjanian, H., Moazzam-Jazi, M., Hedayati, M., Akbarzadeh, M., Guity, K., Sedaghati-Khayat, B., et al. (2021). SARS-CoV-2 infection susceptibility influenced by ACE2 genetic polymorphisms: insights from Tehran cardio-metabolic genetic study. *Sci. Rep.* 11:1529. doi: 10.1038/s41598-020-80325-x

Larsson, P. T., Schwieriel, J. H., and Wallen, N. H. (2000). Platelet activation during angiotensin II infusion in healthy volunteers. Blood Coag. *Fibrinolysis* 11, 61–69. doi: 10.1097/00001721-200011010-00007

Lavrentyev, E. N., and Malik, K. U. (2009). High glucose-induced Nox1-derived superoxides downregulate PKC-βII, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs. *Am. J. Physiol. Circ. Physiol.* 296, H106–H118. doi: 10.1152/ajpheart.00239.2008

Lee, I. I., Nakayama, T., Wu, C. T., Goltsey, Y., Jiang, S., Gall, P. A., et al. (2020). ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. *Nat. Commun.* 11:5453. doi: 10.1038/s41467-020-19145-6

Lei, C., Qian, K., Li, T., Zhang, S., Fu, W., Ding, M., et al. (2020). Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig. *Nat. Commun.* 11:2070. doi: 10.1038/s41467-020-16048-4

Leonard-Lorant, I., Delabranche, X., Severac, F., Helms, J., Pauzet, C., Collange, O., et al. (2020). Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels. *Radiology* 296, E189–E191. doi: 10.1148/radiol.2020201561

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potential key for heterogeneous COVID-19 severity. *Front. Immunol.* 11:586111.
doi: 10.3389/fimmu.2020.586111

Kario, K., Hoshide, S., Umeda, Y., Sato, Y., Ikeda, U., Nishiuma, S., et al. (1999).
Angiotensinogen and angiotensin-converting enzyme genotypes, and day and night
blood pressures in elderly Japanese hypertensives. *Hypertens. Res.* 22, 95–103. doi:
10.1291/hypres.22.95

Karnik, S. S., Singh, K. D., Tirupula, K., and Unal, H. (2017). Significance of angiotensin 1-7 coupling with MAS1 receptor and other GPGs to the renin-angiotensin system: IUPHAR review 22. *Br. J. Pharmacol.* 174, 737–753. doi: 10.1111/bph.13742

Kassan, M., Ait-Aissa, K., Radwan, E., Mali, V., Haddox, S., Gabani, M., et al. (2016). Essential role of smooth muscle STIM1 in hypertension and cardiovascular dysfunction. *Arterioscler. Thromb. Vasc. Biol.* 36, 1900–1909. doi: 10.1161/
ATVBAHA.116.307869

Kassan, M., Galán, M., Partyka, M., Saifudeen, Z., Henrion, D., Trebak, M., et al. (2012). Endoplasmic reticulum stress is involved in cardiac damage and vascular endothelial dysfunction in hypertensive mice. *Arterioscler. Thromb. Vasc. Biol.* 32, 1652–1661. doi: 10.1161/ATVBAHA.112.249318

Katsoularis, I., Fonseca-Rodriguez, O., Farrington, P., Jerndal, H., Häggström Lundevaller, E., Sund, M., et al. (2022). Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study. *BMJ* 377:e069590. doi: 10.1136/bmj-2021-069590

Kellam, P., and Barclay, W. (2020). The dynamics of humoral immune responses following SARS-CoV-2 infection and the potential for reinfection. *J. Gen. Virol.* 101, 791–797. doi: 10.1099/jgv.0.001439

Khaddaj-Mallat, R., Aldib, N., Bernard, M., Paquette, A. S., Ferreira, A., Lecordier, S., et al. (2021). SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via spike protein. *Neurobiol. Dis.* 161:105561. doi: 10.1016/j.nbd.2021.105561

Khan, A., Benthin, C., Zeno, B., Albertson, T. E., Boyd, J., Christie, J. D., et al. (2017). A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. *Crit. Care* 21:234. doi: 10.1186/
s13054-017-1823-x

Khayat, AS, de Assumpc, PP, Meireles Khayat, BC, Thomaz Arau Jo, TM,
Batista-Gomes, JA, Imbiriba, L.C., et al. (2020). ACE2 polymorphisms as potential
players in COVID-19 outcome. *PLoS One* 15:e0243887. doi: 10.1371/journal.
pone.024388

Kintscher, U., Slagman, A., Domenig, O., Röhle, R., Konietschke, F., Poglitsch, M., et al. (2020). Plasma angiotensin peptide profiling and ACE (angiotensin-converting enzyme)-2 activity in COVID-19 patients treated with pharmacological blockers of the renin-angiotensin system. *Hypertension* 76, e34–e36. doi: 10.1161/
HYPERTENSIONAHA.120.15841

Kliche, J., Kuss, H., Ali, M., and Ivarsson, Y. (2021). Cytoplasmic short linear motifs in ACE2 and integrin β3 link SARS-CoV-2 host cell receptors to mediators of endocytosis and autophagy. *Sci. Signal.* 14:ebaf1117. doi: 10.1126/scisignal.
abf1117

Kok, K. H., Wong, S. C., Chan, W. M., Lei, W., Chu, A. W. H., Ip, J. D., et al. (2022). Cocirculation of two SARSCoV-2 variant strains within imported pet hamsters in Hong Kong. *Emerg. Microb. Infect.* 11, 689–698. doi: 10.1080/
22221751.2022.2040922

Koka, V., Huang, X. R., Chung, A. C. K., Wang, W., Truong, L. D., and Lan, H. Y. (2008). Angiotensin II up-regulates angiotensin I converting enzyme (ACE), but Down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. *Am. J. Pathol.* 172, 1174–1183. doi: 10.2353/ajpath.2008.070762

Kougias, P., Chai, H., Lin, P. H., Yao, Q., Lumsden, A. B., and Chen, C. (2005).
Defensins and cathelicidins: neutrophil peptides with roles in inflammation,
hyperlipidemia and atherosclerosis. *J. Cell. Mol. Med.* 9, 3–10. doi: 10.1111/j.1582-4934.2005.tb00332.x

Kragstrup, T. W, Sogaard Singh, H., Grundberg, I., Langkilde-Lauesen Nielsen, A., Rivellese, F, Mehta, A., et al. (2021). Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients. *PLoS One* 16:e0252799. doi: 10.1371/journal.
pone.0252799

Krishnamurthy, S., Lockey, R. F., and Kolliputi, N. (2021). Soluble ACE2 as a potential therapy for COVID-19. *Am. J. Phys. Cell Physiol.* 320, C279–C281. doi: 10.1152/ajpcell.00478.2020

Ksiazek, T. G., Erdman, D., Goldsmith, C. S., Zaki, S. R., Peret, T., Emery, S., et al. (2003). A novel coronavirus associated with severe acute respiratory syndrome. *N. Engl. J. Med.* 348, 1953–1966. doi: 10.1056/NEJMoa030781

Kuan, T. C., Yang, T. H., Wen, C. H., Chen, M. Y., Lee, I. L., and Lin, C. S. (2011). Identifying the regulatory element for human angiotensin-converting enzyme 2 (ACE2) expression in human cardiofibroblasts. *Peptides* 32, 1832–1839. doi: 10.1016/j.peptides.2011.08.009

Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., et al. (2005). A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. *Nat. Med.* 11, 875–879. doi: 10.1038/nm1267

Kulemina, L. V., and Ostrov, D. A. (2011). Prediction of off-target effects on angiotensin-converting enzyme 2. *J. Biomol. Screen.* 16, 878–885. doi: 10.1177/1087057111413919

Kundura, L., Gimenez, S., Cezar, R., André, S., Younas, M., Lin, Y. L., et al. (2022). Angiotensin II induces reactive oxygen species, DNA damage, and T-cell apoptosis in severe COVID-19. *J. Allergy Clin. Immunol.* 150, 594–603.e2. doi: 10.1016/j.jaci.2022.06.020

Kwakernaak, A. J., Roksnoer, L. C., Lambers Heerspink, H. J., Ven den Berg-Garrelds, I., Lochorn, G. A., Embden, J. H., et al. (2017). Effects of direct renin blockade on renal & systemic hemodynamics and on RAAS activity, in weight excess and hypertension: a randomized clinical trial. *PLoS One* 12:e0169258. doi: 10.1371/journal.pone.0169258

Lam, S. D., Bordin, N., Waman, V. P., Scholes, H. M., Ashford, P., Sen, N., et al. (2020). SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals. *Sci. Rep.* 10:16471. doi: 10.1038/s41598-020-71936-5

Lambert, D. W., Clarke, N. E., Hooper, N. M., and Turner, A. J. (2008). Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain. *FEBS Lett.* 582, 385–390. doi: 10.1016/j.febslet.2007.11.085

Lambert, D. W., Yarski, M., and Warner, F. J. (2005). Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). *J. Biol. Chem.* 280, 30113–33019. doi: 10.1074/jbc.M505111200

Lamers, M. M., Beumer, J., van der Vaart, J., Knoops, K., Puschhof, J., Breugem, T. I., et al. (2020). SARS-CoV-2 productively infects human gut enterocytes. *Science* 369, 50–54. doi: 10.1126/science.abc1669

Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., et al. (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. *Nature* 581, 215–220. doi: 10.1038/s41586-020-2180-5

Lanjanian, H., Moazzam-Jazi, M., Hedayati, M., Akbarzadeh, M., Guity, K., Sedaghati-Khayat, B., et al. (2021). SARS-CoV-2 infection susceptibility influenced by ACE2 genetic polymorphisms: insights from Tehran cardio-metabolic genetic study. *Sci. Rep.* 11:1529. doi: 10.1038/s41598-020-80325-x

Larsson, P. T., Schwieriel, J. H., and Wallen, N. H. (2000). Platelet activation during angiotensin II infusion in healthy volunteers. Blood Coag. *Fibrinolysis* 11, 61–69. doi: 10.1097/00001721-200011010-00007

Lavrentyev, E. N., and Malik, K. U. (2009). High glucose-induced Nox1-derived superoxides downregulate PKC-βII, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs. *Am. J. Physiol. Circ. Physiol.* 296, H106-H118. doi: 10.1152/ajpheart.00239.2008

Lee, I. I., Nakayama, T., Wu, C. T., Toltsey, Y., Jiang, S., Gall, P. A., et al. (2020). ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. *Nat. Commun.* 11:5453. doi: 10.1038/s41467-020-19145-6

Lei, C., Qian, K., Li, T., Zhang, S., Fu, W., Ding, M., et al. (2020). Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig. *Nat. Commun.* 11:2070. doi: 10.1038/s41467-020-16048-4

Leonard-Lorant, I., Delabranche, X., Severac, F., Helms, J., Pauzet, C., Collange, O., et al. (2020). Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels. *Radiology* 296, E189–E191. doi: 10.1148/radiol.2020201561

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Liu, C., Li, Y., Guan, T., Lai, Y., Shen, Y., Zeyaweiding, A., et al. (2018). ACE2 polymorphisms associated with cardiovascular risk in Uygurs with type 2 diabetes mellitus. *Cardiovasc. Diabetol.* 17:127. doi: 10.1186/s12933-018-0771-3

Liu, C., Luo, R., Elliott, S. E., Wang, W., Parchim, N. F., Iriyama, T., et al. (2015). Elevated transglutaminase activity triggers angiotensin receptor activating autoantibody production and pathophysiology of preeclampsia. *J. Am. Heart Assoc.* 4:e002323. doi: 10.1161/JAHA.115.002323

Liu, P., Wysocki, J., Souma, T., Ye, M., Ramirez, V., Zhou, B., et al. (2018). Novel ACE2-fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation. *Kidney Int.* 94, 114–125. doi: 10.1016/j.kint.2018.01.029

Liu, Y., Yang, Y., Zhang, C., Huang, F., Wang, F., Yuan, J., et al. (2020). Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. *Sci. China Life Sci.* 63, 364–374. doi: 10.1007/s11427-020-1643-8

Liu, Y., and Zhang, H. G. (2021). Vigilance on new-onset atherosclerosis following SARS-CoV-2 infection. *Front. Med.* 7:629413. doi: 10.3389/fmed.2020.629413

Long, Q. X., Liu, B. Z., Deng, H. J., Wu, G. C., Deng, K., Chen, Y. K., et al. (2020). Antibody responses to SARS-CoV-2 in patients with COVID-19. *Nat. Med.* 26, 845–848. doi: 10.1038/s41591-020-0897-1

Lopez, R. D., Macedo, A. V. S., de Baros, E., Silva, P. G. M., Moll-Bernardes, J., dos Santos, T., et al. (2021). Continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19. A randomized clinical trial. *JAMA* 325, 254–264. doi: 10.1001/jama.2020.25864

Lorente, L., Martin, M. M., Franco, A., Barrios, Y., Caceres, J. J., Solé-Violán, J., et al. (2020). HLA genetic polymorphisms and prognosis of patients with COVID-19. *Med. Int.* 45, 96–103. doi: 10.1016/j.medint.2020.08.004

Luan, J., Lu, Y., Jin, X., and Zhang, L. (2020). Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection. *Biochem. Biophys. Res. Commun.* 526, 165–169. doi: 10.1016/j. bbrc.2020.03.047

Lubbe, L., Cozier, G. E., Dosthuizen, D., Acharya, K. R., and Sturrock, E. D. (2020). ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV. *Clin. Sci.* 134, 2851–2871. doi: 10.1042/ CS20200899

Luo, Y., Liu, C., Guan, T., Li, Y., Lai, Y., Li, F., et al. (2019). Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in South Xinjiang. *Hypertens. Res.* 42, 681–689. doi: 10.1038/s41440-018-0166-6

Luo, Y., Mao, L., Yan, X., Xue, Y., Lin, Q., Tang, G., et al. (2020). Predicted model based on the combination of cytokines and lymphocytes subsets for prognosis of SARS-CoV-2 infection. *J. Clin. Immunol.* 40, 960–969. doi: 10.1007/ s10875-020-00821-7

Luther, J. M., Gainer, J. V., Murphey, L. J., Yu, C., Vaughan, D. E., Morrow, J. D., et al. (2006). *Hypertension* 48, 1050–1057. doi: 10.1161/01.HYP.0000248135.97380.6

Lv, Y., Li, Y., Yi, Y., Zhang, L., Shi, Q., and Yang, J. (2018). A genomic survey of angiotensin-converting enzymes provides novel insights into their molecular evolution in vertebrates. *MoLECULES* 23:2923. doi: 10.3390/molecules23112923

Ma, H., Zeng, W., He, H., Zhao, D., Jiang, D., Zhou, P., et al. (2020). Serum IgA, IgM, and IgG responses in COVID-19. *Cell. Mol. Immunol.* 17, 773–775. doi: 10.1038/s41423-020-0474-z

Magro, C., Mulvey, J. J., Berlin, D., Nuovo, G., Salvatore, S., Harp, J., et al. (2020). Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. *Transl. Res.* 220, 1–13. doi: 10.1016/j.trsl.2020.04.007

Maiti, B. K. (2021). Bioengineered angiotensin-converting-enzyme-2: a potential therapeutic option against SARS-CoV-2 infection. *J. Hum. Hypertens.* 36, 488–492. doi: 10.1038/s41371-021-00636-y

Manne, B. K., Denorme, F., Middleton, E. A., Portier, I., Rowley, J. W., Stubben, C. J., et al. (2020). Platelet gene expression and function in COVID-19 patients. *Blood* 136, 1317–1329. doi: 10.1182/-blood.2020007214

Marchiano, S., Hsiang, T. Y., Khanna, A., Higashi, T., Whitmore, L. S., Bargehr, J., et al. (2021). SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function. *Cell Stem Rep.* 16, 478–492. doi: 10.1016/j stemcr.2021.02.008

Marian, A. J. (2013). The discovery of the ACE2 gene. *Circ. Res.* 112, 1307–1309. doi: 10.1161/CIRCRESAHA.113.301271

Marra, M. A., Jones, S. J., Astell, C. R., Holt, R. A., Brooks-Wilson, A., Butterfield, Y. S., et al. (2003). The genome sequence of the SARS-associated coronavirus. *Science* 300, 1399–1404. doi: 10.1126/science.1085953

Marshall, R. P., Webb, S., Bellingan, G. J., Montgomery, H. E., Chaudhari, B., Mc Arthur, R. J., et al. (2002). Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. *Am. J. Respir. Crit. Care Med.* 166, 646–650. doi: 10.1164/ rccm.2108086

Martinez, E., Pura, A., Escribano, J., Sanchis, C., Carrion, L., Artigao, M., et al. (2000). Angiotensin-converting enzyme (ACE) gene polymorphisms, serum ACE activity and blood pressure in a Spanish-Mediterranean population. *J. Hum. Hypertens.* 14, 131–135. doi: 10.1038/sj.jhh.1000958

Martinez-Rojas, M. A., Vega-Vega, O., and Bobadilla, X. N. A. (2020). Is the kidney a target of SARS-CoV-2? *Am. J. Physiol. Ren. Physiol.* 318, F1454–F1462. doi: 10.1152/AJPRENAL.00160.2

Martins, A. L. V., da Silva, F. A., Bolais-Ramos, L., Capanema de Oliveira, G., Cunha Ribeiro, R., Alves Pereira, D. A., et al. (2021). Increased circulating levels of angiotensin-(1-7) in severely ill COVID-19 patients. *ERJ Open Res.* 7, 00114–02021. doi: 10.1183/23120541.00114-2021

Martin-Sanchos, L., Lewinski, M. K., Pache, L., Stoneham, C. A., Yin, X., Becker, M., et al. (2021). Functional landscape of SARS-CoV-2 cellular restriction. *Mol. Cell* 81, 2656–2668.e8. doi: 10.1016/j.molcel.2021.04.008

Massiéra, F., Bloch-Faure, M., Ceiler, D., Murakami, K., Fukamizu, A., Gasc, J.-M., et al. (2001). Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. *FASEB J.* 15, 2727–2729. doi: 10.1096/fj.01-0457fje

Mecca, A. P., Regenhardt, R. W., O'Connor, T. E., Jospeh, J. P., Raizada, M. K., Katovich, M. J., et al. (2011). Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke. *Exp. Physiol.* 96, 1084–1096. doi: 10.1113/ exphysiol.2011.058758

Mehta, P., Mc Autley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., Manson, J. J., et al. (2020). COVID-19: consider cytokine storm syndromes and immunosuppression. *Lancet* 395, 1033–1034. doi: 10.1016/S0140-6736(20)30628-0

Meng, J., Xiao, G., Zhang, J., He, X., Ou, M., Bi, J., et al. (2020). Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. *Emerg. Microb. Infect.* 9, 757–760. doi: 10.1080/22221751.2020.1746200

Meng, N., Zhang, Y., Ma, J., Li, H., Zhou, F., and Qu, Y. (2015). Association of polymorphisms of angiotensin I converting enzyme 2 with retinopathy in type 2 diabetes mellitus among Chinese individuals. *Eye* 29, 266–271. doi: 10.1038/ eye.2014.254

Mentz, R. J., Bakris, G. L., Waeber, B., McMurray, J. J., Gheorghiade, M., Ruilope, L. M., et al. (2013). The past, present and future of renin-angiotensin aldosterone system inhibition. *Int. J. Cardiol.* 167, 1677–1687. doi: 10.1016/j. icjard.2012.10.007

Middeldorp, S., Coppens, M., van Haaps, T. F., Foppen, M., Vlaar, A. P., Miller, M. C. A., et al. (2020). Incidence of venous thromboembolism in hospitalized patients with COVID-19. *J. Thromb. Haemost.* 18, 1995–2002. doi: 10.1111/jth.14888

Miedema, J., Schreurs, M., van der Sarvan der Brugge, S., Paats, M., Baart, S., Bakker, M., et al. (2021). Antibodies against angiotensin II receptor type 1 and endothelin a receptor are associated with an unfavorable COVID19 disease course. *Front. Immunol.* 12:684142. doi: 10.3389/fimmu.2021.684142

Minato, T., Nirasawa, S., Sato, T., Yamaguchi, T., Hoshizaki, M., Inagaki, T., et al. (2020). B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction. *Nat. Commun.* 11:1058. doi: 10.1038/ s41467-020-14867-z

Mizuiri, S., Hemmi, H., Arita, M., Ohashi, Y., Tanaka, Y., Miyagi, M., et al. (2008). Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls. *Am. J. Kidney Dis.* 51, 613–623. doi: 10.1053/j.ajkd.2007.11.022

Möhlendick, B., Schönfelder, K., Breuckmann, K., Elsner, C., Babel, N., Balfanz, P., et al. (2021). ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19. *Pharmacogenet. Genomics* 31, 165–171. doi: 10.1097/ FPC.0000000000000436

Montagutelli, X, Prot, M, Levillayer, L, Baquero SAlazar, E, Jouvion, G, Conquart, L., et al. The B1.351 and P. 1 variants extend SARS-CoV-2 host range to mice. bioRxiv [Preprint]. (2021). doi: 10.1101/2021.03.18.436013

Monteil, V., Dyczynski, M., Lauschke, V. M., Kwon, H., Wirnsberger, G., Youhanna, S., et al. (2021). Human soluble ACE2 improves the effect of remdesvirin in SARS-CoV-2 infection. *EMBO Mol. Med.* 13:e13426. doi: 10.15252/ emmm.202013426

Moore, J. P., Vinh, A., Tuck, K., Sakkal, S., Krishnan, S. M., Chan, C. T., et al. (2015). M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure. *Am. J. Physiol. Circ. Physiol.* 309, H906–H917. doi: 10.1152/apjheart.00821.2014

Muller, D. N., Hilgers, K. F., Mathews, S., Breu, V., Fischli, W., Uhlmann, R., et al. (1999). Effects of human prorinin in rats transgenic for human angiotensinogen. *Hypertension* 33, 312–317. doi: 10.1161/01.HYP.33.1.312

Muller, D. N., Mervaala, E. M. A., Dechend, R., Fiebeler, A., Park, J. K., Schmidt, F., et al. (2000). Angiotensin II (AT₂) receptor blockade reduces vascular tissue factor
Liu, Y., Hu, G., Wang, Y., Ren, W., Zhao, X., Ji, F., et al. (2021). Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2. *Proc. Natl. Acad. Sci. U. S. A.* 118:e2025373118. doi: 10.1073/ pnas.2025373118

Liu, C., Li, Y., Guan, T., Lai, Y., Shen, Y., Zeyaweiding, A., et al. (2018). ACE2 polymorphisms associated with cardiovascular risk in Uygurs with type 2 diabetes mellitus. *Cardiovasc. Diabetol.* 17:127. doi: 10.1186/s12933-018-0771-3

Liu, C., Luo, R., Elliott, S. E., Wang, W., Parchim, N. F., Iriyama, T., et al. (2015). Elevated transglutaminase activity triggers angiotensin receptor activating autoantibody production and pathophysiology of preeclampsia. *J. Am. Heart Assoc.* 4:e002323. doi: 10.1161/JAHA.115.002323

Liu, P., Wysocki, J., Souma, T., Ye, M., Ramirez, V., Zhou, B., et al. (2018). Novel ACE2-fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation. *Kidney Int.* 94, 114–125. doi: 10.1016/j.kint.2018.01.029

Liu, Y., Yang, Y., Zhang, C., Huang, F., Wang, F., Yuan, J., et al. (2020). Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. *Sci. China Life Sci.* 63, 364–374. doi: 10.1007/s11427-020-1643-8

Liu, Y., and Zhang, H. G. (2021). Vigilance on new-onset atherosclerosis following SARS-CoV-2 infection. *Front. Med.* 7:629413. doi: 10.3389/fmed.2020.629413

Long, Q. X., Liu, B. Z., Deng, H. J., Wu, G. C., Deng, K., Chen, Y. K., et al. (2020). Antibody responses to SARS-CoV-2 in patients with COVID-19. *Nat. Med.* 26, 845–848. doi: 10.1038/s41591-020-0897-1

Lopez, R. D., Macedo, A. V. S., de Baros, E., Silva, P. G. M., Moll-Bernardes, J., dos Santos, T., et al. (2021). Continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19. A randomized clinical trial. *JAMA* 325, 254–264. doi: 10.1001/jama.2020.25864

Lorente, L., Martin, M. M., Franco, A., Barrios, Y., Caceres, J. J., Solé-Violán, J., et al. (2020). HLA genetic polymorphisms and prognosis of patients with COVID-19. *Med. Int.* 45, 96–103. doi: 10.1016/j.medint.2020.08.004

Luan, J., Lu, Y., Jin, X., and Zhang, L. (2020). Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection. *Biochem. Biophys. Res. Commun.* 526, 165–169. doi: 10.1016/j. bbrc.2020.03.047

Lubbe, L., Cozier, G. E., Dosthuizen, D., Acharya, K. R., and Sturrock, E. D. (2020). ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV. *Clin. Sci.* 134, 2851–2871. doi: 10.1042/ CS20200899

Luo, Y., Liu, C., Guan, T., Li, Y., Lai, Y., Li, F., et al. (2019). Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in South Xinjiang. *Hypertens. Res.* 42, 681–689. doi: 10.1038/s41440-018-0166-6

Luo, Y., Mao, L., Yan, X., Xue, Y., Lin, Q., Tang, G., et al. (2020). Predicted model based on the combination of cytokines and lymphocytes subsets for prognosis of SARS-CoV-2 infection. *J. Clin. Immunol.* 40, 960–969. doi: 10.1007/ s10875-020-00821-7

Luther, J. M., Gainer, J. V., Murphey, L. J., Yu, C., Vaughan, D. E., Morrow, J. D., et al. (2006). *Hypertension* 48, 1050–1057. doi: 10.1161/01.HYP.0000248135.97380.6

Lv, Y., Li, Y., Yi, Y., Zhang, L., Shi, Q., and Yang, J. (2018). A genomic survey of angiotensin-converting enzymes provides novel insights into their molecular evolution in vertebrates. *MoLECULES* 23:2923. doi: 10.3390/molecules23112923

Ma, H., Zeng, W., He, H., Zhao, D., Jiang, D., Zhou, P., et al. (2020). Serum IgA, IgM, and IgG responses in COVID-19. *Cell. Mol. Immunol.* 17, 773–775. doi: 10.1038/s41423-020-0474-z

Magro, C., Mulvey, J. J., Berlin, D., Nuovo, G., Salvatore, S., Harp, J., et al. (2020). Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. *Transl. Res.* 220, 1–13. doi: 10.1016/j.trsl.2020.04.007

Maiti, B. K. (2021). Bioengineered angiotensin-converting-enzyme-2: a potential therapeutic option against SARS-CoV-2 infection. *J. Hum. Hypertens.* 36, 488–492. doi: 10.1038/s41371-021-00636-y

Manne, B. K., Denorme, F., Middleton, E. A., Portier, I., Rowley, J. W., Stubben, C. J., et al. (2020). Platelet gene expression and function in COVID-19 patients. *Blood* 136, 1317–1329. doi: 10.1182/-blood.2020007214

Marchiano, S., Hsiang, T. Y., Khanna, A., Higashi, T., Whitmore, L. S., Bargehr, J., et al. (2021). SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function. *Cell Stem Rep.* 16, 478–492. doi: 10.1016/j stemcr.2021.02.008

Marian, A. J. (2013). The discovery of the ACE2 gene. *Circ. Res.* 112, 1307–1309. doi: 10.1161/CIRCRESAHA.113.301271

Marra, M. A., Jones, S. J., Astell, C. R., Holt, R. A., Brooks-Wilson, A., Butterfield, Y. S., et al. (2003). The genome sequence of the SARS-associated coronavirus. *Science* 300, 1399–1404. doi: 10.1126/science.1085953

Marshall, R. P., Webb, S., Bellingan, G. J., Montgomery, H. E., Chaudhari, B., Mc Arthur, R. J., et al. (2002). Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. *Am. J. Respir. Crit. Care Med.* 166, 646–650. doi: 10.1164/ rccm.2108086

Martinez, E., Pura, A., Escribano, J., Sanchis, C., Carrion, L., Artigao, M., et al. (2000). Angiotensin-converting enzyme (ACE) gene polymorphisms, serum ACE activity and blood pressure in a Spanish-Mediterranean population. *J. Hum. Hypertens.* 14, 131–135. doi: 10.1038/sj.jhh.1000958

Martinez-Rojas, M. A., Vega-Vega, O., and Bobadilla, X. N. A. (2020). Is the kidney a target of SARS-CoV-2? *Am. J. Physiol. Ren. Physiol.* 318, F1454–F1462. doi: 10.1152/AJPRENAL.00160.2

Martins, A. L. V., da Silva, F. A., Bolais-Ramos, L., Capanema de Oliveira, G., Cunha Ribeiro, R., Alves Pereira, D. A., et al. (2021). Increased circulating levels of angiotensin-(1-7) in severely ill COVID-19 patients. *ERJ Open Res.* 7, 00114–02021. doi: 10.1183/23120541.00114-2021

Martin-Sanchos, L., Lewinski, M. K., Pache, L., Stoneham, C. A., Yin, X., Becker, M., et al. (2021). Functional landscape of SARS-CoV-2 cellular restriction. *Mol. Cell* 81, 2656–2668.e8. doi: 10.1016/j.molcel.2021.04.008

Massiéra, F., Bloch-Faure, M., Ceiler, D., Murakami, K., Fukamizu, A., Gasc, J.-M., et al. (2001). Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. *FASEB J.* 15, 2727–2729. doi: 10.1096/fj.01-0457fje

Mecca, A. P., Regenhardt, R. W., O'Connor, T. E., Jospeh, J. P., Raizada, M. K., Katovich, M. J., et al. (2011). Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke. *Exp. Physiol.* 96, 1084–1096. doi: 10.1113/ exphysiol.2011.058758

Mehta, P., Mc Autley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., Manson, J. J., et al. (2020). COVID-19: consider cytokine storm syndromes and immunosuppression. *Lancet* 395, 1033–1034. doi: 10.1016/S0140-6736(20)30628-0

Meng, J., Xiao, G., Zhang, J., He, X., Ou, M., Bi, J., et al. (2020). Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. *Emerg. Microb. Infect.* 9, 757–760. doi: 10.1080/22221751.2020.1746200

Meng, N., Zhang, Y., Ma, J., Li, H., Zhou, F., and Qu, Y. (2015). Association of polymorphisms of angiotensin I converting enzyme 2 with retinopathy in type 2 diabetes mellitus among Chinese individuals. *Eye* 29, 266–271. doi: 10.1038/ eye.2014.254

Mentz, R. J., Bakris, G. L., Waeber, B., McMurray, J. J., Gheorghiade, M., Ruilope, L. M., et al. (2013). The past, present and future of renin-angiotensin aldosterone system inhibition. *Int. J. Cardiol.* 167, 1677–1687. doi: 10.1016/j. ijcard.2012.10.007

Middeldorp, S., Coppens, M., van Haaps, T. F., Foppen, M., Vlaar, A. P., Miller, M. C. A., et al. (2020). Incidence of venous thromboembolism in hospitalized patients with COVID-19. *J. Thromb. Haemost.* 18, 1995–2002. doi: 10.1111/jth.14888

Miedema, J., Schreurs, M., van der Sarvan der Brugge, S., Paats, M., Baart, S., Bakker, M., et al. (2021). Antibodies against angiotensin II receptor type 1 and endothelin a receptor are associated with an unfavorable COVID19 disease course. *Front. Immunol.* 12:684142. doi: 10.3389/fimmu.2021.684142

Minato, T., Nirasawa, S., Sato, T., Yamaguchi, T., Hoshizaki, M., Inagaki, T., et al. (2020). B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction. *Nat. Commun.* 11:1058. doi: 10.1038/ s41467-020-14867-z

Mizuiri, S., Hemmi, H., Arita, M., Ohashi, Y., Tanaka, Y., Miyagi, M., et al. (2008). Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls. *Am. J. Kidney Dis.* 51, 613–623. doi: 10.1053/j.ajkd.2007.11.022

Möhlendick, B., Schönfelder, K., Breuckmann, K., Elsner, C., Babel, N., Balfanz, P., et al. (2021). ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19. *Pharmacogenet. Genomics* 31, 165–171. doi: 10.1097/ FPC.0000000000000436

Montagutelli, X, Prot, M, Levillayer, L, Baquero SAlazar, E, Jouvion, G, Conquart, L., et al. The B1.351 and P. 1 variants extend SARS-CoV-2 host range to mice. bioRxiv [Preprint]. (2021). doi: 10.1101/2021.03.18.436013

Monteil, V., Dyczynski, M., Lauschke, V. M., Kwon, H., Wirnsberger, G., Youhanna, S., et al. (2021). Human soluble ACE2 improves the effect of remdesvirin in SARS-CoV-2 infection. *EMBO Mol. Med.* 13:e13426. doi: 10.15252/ emmm.202013426

Moore, J. P., Vinh, A., Tuck, K., Sakkal, S., Krishnan, S. M., Chan, C. T., et al. (2015). M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure. *Am. J. Physiol. Circ. Physiol.* 309, H906–H917. doi: 10.1152/apjheart.00821.2014

Muller, D. N., Hilgers, K. F., Mathews, S., Breu, V., Fischli, W., Uhlmann, R., et al. (1999). Effects of human prorinin in rats transgenic for human angiotensinogen. *Hypertension* 33, 312–317. doi: 10.1161/01.HYP.33.1.312

Muller, D. N., Mervaala, E. M. A., Dechend, R., Fiebeler, A., Park, J. K., Schmidt, F., et al. (2000). Angiotensin II (AT₂) receptor blockade reduces vascular tissue factor
in angiotensin II-induced cardiac vasculopathy. Am. J. Pathol. 157, 111-122. doi: 10.1016/S0002-9440(10)64523-3

Mullick, A. E., Yeh, S. T., Graham, M. J., Engelhardt, J. A., Prakash, T. P., and Crooke, R. M. (2017). Blood pressure lowering and safety improvements with liver angiotensinogen inhibition in models of hypertension and kidney injury. *Hypertension* 70, 566-576. doi: 10.1161/HYPERTENSIONAHA.117.09755

Murphy, T. J., Alexander, R. W., Griendling, K. K., Runge, M. S., and Bernstein, K. E. (1991). Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. *Nature* 351, 233-236. doi: 10.1038/351233a0

Muus, C., Luecken, M., Eraslan, G., Waghray, A., Heimberg, G., Sikkema, L., et al. (2020). Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells. bioRxiv [Preprint]. doi: 10.1101/2020.04.19.049254

Nabah, Y. N. A., Mateo, T., Estellés, R., Mata, M., Zagorski, J., Sarau, H., et al. (2004). Angiotensin II induces neutrophil accumulation in vivo through generation and release of CXC chemokines. *Circulation* 110, 3581-3586. doi: 10.1161/01.CIR.0000148824.93600. F3

Naftilan, A. J., and Oparil, S. (1978). Inhibition of renin release from rat kidney slices by the angiotensins. Am. J. Phys. 235, F62-F68. doi: 10.1152/aprenal.1978.235.1.F62

Nassar, H., Lavi, E., Akkawi, S., Bdeir, K., Heyman, S. M., Raghunath, P. N., et al. (2007). Alpha-Defensin: link between inflammation and atherosclerosis. *Atherosclerosis* 194, 452-457. doi: 10.1016/j.atherosclerosis.2006.08.046

Nataraj, C., Oliverio, M. I., Mannon, R. B., Mannon, P. J., Audoly, L. P., Amuchastegui, C. S., et al. (1999). Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J. Clin. Invest. 104, 1693-1701. doi: 10.1172/JCI17451

Nemerson, Y. (1988). Tissue factor and hemostasis. Blood 71, 1-8. doi: 10.1182/blood.V71.1.1.1

Neves, F. A., Duncan, K. G., and Baxter, J. D. (1996). Cathepsin B is a prorenin processing enzyme. Hypertension 27, 514-517. doi: 10.1161/01.hyp.27.3.514

Nguyen, A., David, J. K., Maden, S. K., Wood, M. A., Weeder, B. R., Nellore, A., et al. (2020). Human leukocyte antigen susceptibility map for severe acute respiratory syndrome coronavirus 2. J. Virol. 94, e00510-e00520. doi: 10.1128/JVI.00510-20

Nguyen, G., Delarue, F., Burcklé, C., Bouzhir, L., Giller, T., and Sraer, J. D. (2002). Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417-1427. doi: 10.1172/JCI14276

Nikiforuk, A. M., Kuchinski, K. S., Twa, D. D. W., Lukac, C. D., Sbihi, H., Basham, C. A., et al. (2021). The contrasting role of nasopharyngeal angiotensin converting enzyme 2 (ACE2) expression in SARS-CoV-2 infection: a cross-sectional study of people tested for COVID-19 in British Columbia. EBio Med. 66:103316. doi: 10.1016/j.ebiom.2021.103316

Nishimura, H. (2017). Renin-angiotensin system in vertebrates: phylogenetic view of structure and function. *Anat. Sci. Int.* 92, 215-247. doi: 10.1007/s12565-016-0372-8

Nishimura, H., Tsuji, H., Masuada, H., Nakagawa, K., Nakahara, Y., Kitamura, H., et al. (1997). Angiotensin II increases plasminogen activator Inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. Thromb. Haemost. 77, 1189-1195. doi: 10.1055/s-0038-1656136

Niu, W., Qi, Y., Hou, S., Zhou, W., and Qiu, C. (2007). Correlation of angiotensin-converting enzyme 2 gene polymorphisms with stage 2 hypertension in Han Chinese. Transl. Res. 150, 374-380. doi: 10.1016/j.trsl.2007.06.002

Oarhe, C. I., Dang, V., Dang, M. T., Nguyen, H., Gopallawa, I., Gewolb, I. H., et al. (2015). Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts. *Pediatr. Res.* 77, 656-662. doi: 10.1038/pr.2015.27

Onabajo, O. O., Banday, A. R., Stanifer, M. L., Yan, W., Obajemu, A., Santer, D. M., et al. (2020). Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor. Nat. Genet. 52, 1283-1293. doi: 10.1038/s41588-020-00731-9

Ortiz, M. E., Thurman, A., Pezzulo, A. A., Leidinger, M. R., Klesney-Tait, J. A., Karp, P. H., et al. (2020). Heterogeneous expression of the SARS Coronavirus-2 receptor ACE2 in the human respiratory tract. EBioMed. 60:102976. doi: 10.1016/j.ebiom.2020.102976

Ortiz-Fernández, L., and Sawalha, A. H. (2020). Genetic variability in the expression of the SARS-CoV-2 host cell entry factors across populations. Genes Immun. 21, 269-272. doi: 10.1038/s41435-020-0107-7

Osman, I. O., Garrec, C., de Souza, G. A. P., Zarubica, A., Belhaouari, D. B., Baudoin, J.-P., et al. (2022). Control of CDH1/E-cadherin gene expression and release of a soluble form of E-cadherin in SARS-CoV-2 infected Caco-2 intestinal cells: Physiopathological consequences for the intestinal forms of COVID-19. Front. Cell. Infect. Microbiol. 12:798767. doi: 10.3389/fcimb.2022.798767

Osman, I. O., Melenotte, C., Brouqui, P., Million, M., Lagier, J.-C., Parola, P., et al. (2021). Expression of ACE2, soluble ACE2, angiotensin I, angiotensin II and angiotensin-(1-7) is modulated in COVID-19 patients. Front. Immunol. 12:625732. doi: 10.3389/fimmu.2021.625732

Othman, H., Bouslama, Z., Brandenburg, J. T., da Rocha, J., Hamdi, Y., Ghedira, K., et al. (2020). Interaction of the spike protein RBD from SARS-CoV-2 with ACE2: similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism. Biochem. Biophys. Res. Commun. 527, 702-708. doi: 10.1016/j.bbrc.2020.05.028

Oude Munnink, B. B., Sikkema, R. S., Nieuwenhuijs, D. F., Molenaar, R. J., Munger, E., Molenkamp, R., et al. (2021). Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans. Science 371, 172-177. doi: 10.1126/science.abe5901

Oudit, G. Y., Crackower, M. A., Backx, P. H., and Penninger, J. M. (2003). The role of ACE2 in cardiovascular physiology. *Trends Cardiovasc. Med.* 13, 93-101. doi: 10.1016/s1050-1738(02)00233-5

Oudit, G. Y., Liu, G. C., Zhong, J., Basu, R., Chow, F. L., Zhou, J., et al. (2010). Human recombinant ACE2 reduces the progression of diabetic nephropathy. *Diabetes* 59, 529-538. doi: 10.2337/db09-1218

Oudit, G. Y., and Pfeffer, M. A. (2020). Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19. Eur. Heart J. 41, 1818-1820. doi: 10.1093/eurheartj/ehaa414

Page, I. H., and Helmer, O. M. (1940). Angiotonin-activator, renin-and angiotonin-inhibitor, and the mechanism of angiotonin tachyphylaxis in normal, hypertensive, and nephrectomized animals. J. Exp. Med. 71, 495-519. doi: 10.1084/jem.71.4.495

Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A., Rawlik, K., Parkinson, N., et al. (2021). Genetic mechanisms of critical illness in Covid-19. Nature 591, 92-98. doi: 10.1038/s41586-020-03065-y

Patel, S. K., Velkoska, E., Freeman, M., Wai, B., Lancefield, T. F., and Burrell, L. M. (2014). From gene to protein - experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension. Front. Physiol. 5:227. doi: 10.3389/fphys.2014.00227

Patel, V. B., Zhong, J. C., Grant, M. B., and Oudit, G. Y. (2016). Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ. Res. 118, 1313-1326. doi: 10.1161/CIRCRESAHA.116.307708

Patnaik, M., Pati, P., Swain, S. N., Mohapatra, M. K., Dwibedi, B., Kar, S. K., et al. (2014). Association of angiotensininconverting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha, India. Ann. Hum. Biol. 41, 145-152. doi: 10.3109/03014460.2013.837195

Paul, M., Poyan Mehr, A., and Kreutz, R. (2006). Physiology of local renin-angiotensin systems. Physiol. Rev. 86, 747-803. doi: 10.1152/physrev.00036.2005

Pedersen, K. B., Chhabra, K. H., Nguyen, V. K., Xia, H., and Lazartigues, E. (2013). The transcription factor HNF1alpha induces expression of angiotensin-converting enzyme 2 (ACE2) in pancreatic islets from evolutionarily conserved promoter motifs. Biochim. Biophys. Acta 1829, 1225-1235. doi: 10.1016/j.bbagrm.2013.09.007

Pena Silva, R. A., Chu, Y., Miller, J. D., Mitchell, I. J., Penninger, J. M., Faraci, F. M., et al. (2012). Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging. Stroke 43, 3358-3363. doi: 10.1161/STROKEAHA.112.667063

Peng, H., Li, W., Seth, D. M., Nair, A. R., Francis, J., and Feng, Y. (2013). (pro)renin receptor mediates both angiotensin II-dependent and-independent oxidative stress in neuronal cells. PLoS One 8:e58339. doi: 10.1371/journal.pone.0058339

Perlot, T., and Penninger, J. M. (2013). ACE2-from the renin-angiotensin system to gut microbiota and malnutrition. *Microbes Infect.* 15, 866-873. doi: 10.1016/j.micinf.2013.08.003

Phillips, M. I., and Schmidt-Ott, K. M. (1999). The discovery of renin 100 years ago. *News Physiol. Sci.* 14, 271-274. doi: 10.1152/physiologyonline.1999.14.6.271

Philogene, M. C., Johnson, T., Vaught, A. J., Zakaria, S., and Fedarko, N. (2019). Antibodies against angiotensin II type 1 and endothelin a receptors: relevance and pathogenicity. Hum. Immunol. 80, 561-567. doi: 10.1016/j.humimm.2019.04.012

Pierce, J. B., Simion, V., Icli, B., Perez-Cremades, D., Cheng, H. S., and Feinberg, M. W. (2020). Computational analysis of targeting SARS-CoV-2, viral entry proteins ACE2 and TMPRSS2, and interferon genes by host MicroRNAs. *Genes (Basel)* 11:1354. doi: 10.3390/genes1111354

Pinheiro, D. S., Santos, R. S., Jardim, P. C. B. V., Silva, E. G., Reis, A. A. S., Pedrino, G. R., et al. (2019). The combination of ACE I/D and ACE2 G8790A polymorphisms reveals susceptibility to hypertension: a genetic association study in Brazilian patients. PLoS One 14:e0221248. doi: 10.1371/journal.pone.0221248

Pinto, B. G. G., Oliveira, A. E. R., Singh, Y., Jimenez, L., Goncalves, A. N. A., Ogava, R. L. T., et al. (2020). ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19. J. Infect. Dis. 222, 556-563. doi: 10.1093/infdis/jiaa332

Pires de Souza, G. A., Osman, I. O., Le Bideau, M., Baudoin, J.-P., Jaafar, R., Devaux, C., et al. (2022). Angiotensin II receptor blockers (ARBs antihypertensive
in angiotensin II-induced cardiac vasculopathy. Am. J. Pathol. 157, 111-122. doi: 10.1016/S0002-9440(10)64523-3

Mullick, A. E., Yeh, S. T., Graham, M. J., Engelhardt, J. A., Prakash, T. P., and Crooke, R. M. (2017). Blood pressure lowering and safety improvements with liver angiotensinogen inhibition in models of hypertension and kidney injury. *Hypertension* 70, 566-576. doi: 10.1161/HYPERTENSIONAHA.117.09755

Murphy, T. J., Alexander, R. W., Griendling, K. K., Runge, M. S., and Bernstein, K. E. (1991). Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. *Nature* 351, 233-236. doi: 10.1038/351233a0

Muus, C., Luecken, M., Eraslan, G., Waghray, A., Heimberg, G., Sikkema, L., et al. (2020). Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells. bioRxiv [Preprint]. doi: 10.1101/2020.04.19.049254

Nabah, Y. N. A., Mateo, T., Estellés, R., Mata, M., Zagorski, J., Sarau, H., et al. (2004). Angiotensin II induces neutrophil accumulation in vivo through generation and release of CXC chemokines. *Circulation* 110, 3581-3586. doi: 10.1161/01.CIR.0000148824.93600. F3

Naftilan, A. J., and Oparil, S. (1978). Inhibition of renin release from rat kidney slices by the angiotensins. Am. J. Phys. 235, F62-F68. doi: 10.1152/aprenal.1978.235.1.F62

Nassar, H., Lavi, E., Akkawi, S., Bdeir, K., Heyman, S. M., Raghunath, P. N., et al. (2007). Alpha-Defensin: link between inflammation and atherosclerosis. *Atherosclerosis* 194, 452-457. doi: 10.1016/j.atherosclerosis.2006.08.046

Nataraj, C., Oliverio, M. I., Mannon, R. B., Mannon, P. J., Audoly, L. P., Amuchastegui, C. S., et al. (1999). Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J. Clin. Invest. 104, 1693-1701. doi: 10.1172/JCI17451

Nemerson, Y. (1988). Tissue factor and hemostasis. Blood 71, 1-8. doi: 10.1182/blood.V71.1.1.1

Neves, F. A., Duncan, K. G., and Baxter, J. D. (1996). Cathepsin B is a prorenin processing enzyme. Hypertension 27, 514-517. doi: 10.1161/01.hyp.27.3.514

Nguyen, A., David, J. K., Maden, S. K., Wood, M. A., Weeder, B. R., Nellore, A., et al. (2020). Human leukocyte antigen susceptibility map for severe acute respiratory syndrome coronavirus 2. J. Virol. 94, e00510-e00520. doi: 10.1128/JVI.00510-20

Nguyen, G., Delarue, F., Burcklé, C., Bouzhir, L., Giller, T., and Sraer, J. D. (2002). Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417-1427. doi: 10.1172/JCI14276

Nikiforuk, A. M., Kuchinski, K. S., Twa, D. D. W., Lukac, C. D., Sbihi, H., Basham, C. A., et al. (2021). The contrasting role of nasopharyngeal angiotensin converting enzyme 2 (ACE2) expression in SARS-CoV-2 infection: a cross-sectional study of people tested for COVID-19 in British Columbia. EBio Med. 66:103316. doi: 10.1016/j.ebiom.2021.103316

Nishimura, H. (2017). Renin-angiotensin system in vertebrates: phylogenetic view of structure and function. *Anat. Sci. Int.* 92, 215-247. doi: 10.1007/s12565-016-0372-8

Nishimura, H., Tsuji, H., Masuada, H., Nakagawa, K., Nakahara, Y., Kitamura, H., et al. (1997). Angiotensin II increases plasminogen activator Inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. *Thromb. Haemost.* 77, 1189-1195. doi: 10.1055/s-0038-1656136

Niu, W., Qi, Y., Hou, S., Zhou, W., and Qiu, C. (2007). Correlation of angiotensin-converting enzyme 2 gene polymorphisms with stage 2 hypertension in Han Chinese. *Transl. Res.* 150, 374-380. doi: 10.1016/j.trsl.2007.06.002

Oarhe, C. I., Dang, V., Dang, M. T., Nguyen, H., Gopallawa, I., Gewolb, I. H., et al. (2015). Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts. *Pediatr. Res.* 77, 656-662. doi: 10.1038/pr.2015.27

Onabajo, O. O., Banday, A. R., Stanifer, M. L., Yan, W., Obajemu, A., Santer, D. M., et al. (2020). Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor. *Nat. Genet.* 52, 1283-1293. doi: 10.1038/s41588-020-00731-9

Ortiz, M. E., Thurman, A., Pezzulo, A. A., Leidinger, M. R., Klesney-Tait, J. A., Karp, P. H., et al. (2020). Heterogeneous expression of the SARS Coronavirus-2 receptor ACE2 in the human respiratory tract. EBioMed. 60:102976. doi: 10.1016/j.ebiom.2020.102976

Ortiz-Fernández, L., and Sawalha, A. H. (2020). Genetic variability in the expression of the SARS-CoV-2 host cell entry factors across populations. *Genes Immun.* 21, 269-272. doi: 10.1038/s41435-020-0107-7

Osman, I. O., Garrec, C., de Souza, G. A. P., Zarubica, A., Belhaouari, D. B., Baudoin, J.-P., et al. (2022). Control of CDH1/E-cadherin gene expression and release of a soluble form of E-cadherin in SARS-CoV-2 infected Caco-2 intestinal cells: Physiopathological consequences for the intestinal forms of COVID-19. *Front. Cell. Infect. Microbiol.* 12:798767. doi: 10.3389/fcimb.2022.798767

Osman, I. O., Melenotte, C., Brouqui, P., Million, M., Lagier, J.-C., Parola, P., et al. (2021). Expression of ACE2, soluble ACE2, angiotensin I, angiotensin II and angiotensin-(1-7) is modulated in COVID-19 patients. *Front. Immunol.* 12:625732. doi: 10.3389/fimmu.2021.625732

Othman, H., Bouslama, Z., Brandenburg, J. T., da Rocha, J., Hamdi, Y., Ghedira, K., et al. (2020). Interaction of the spike protein RBD from SARS-CoV-2 with ACE2: similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism. *Biochem. Biophys. Res. Commun.* 527, 702-708. doi: 10.1016/j.bbrc.2020.05.028

Oude Munnink, B. B., Sikkema, R. S., Nieuwenhuijs, D. F., Molenaar, R. J., Munger, E., Molenkamp, R., et al. (2021). Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans. *Science* 371, 172-177. doi: 10.1126/science.abe5901

Oudit, G. Y., Crackower, M. A., Backx, P. H., and Penninger, J. M. (2003). The role of ACE2 in cardiovascular physiology. *Trends Cardiovasc. Med.* 13, 93-101. doi: 10.1016/s1050-1738(02)00233-5

Oudit, G. Y., Liu, G. C., Zhong, J., Basu, R., Chow, F. L., Zhou, J., et al. (2010). Human recombinant ACE2 reduces the progression of diabetic nephropathy. *Diabetes* 59, 529-538. doi: 10.2337/db09-1218

Oudit, G. Y., and Pfeffer, M. A. (2020). Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19. *Eur. Heart J.* 41, 1818-1820. doi: 10.1093/eurheartj/ehaa414

Page, I. H., and Helmer, O. M. (1940). Angiotonin-activator, renin-and angiotonin-inhibitor, and the mechanism of angiotonin tachyphylaxis in normal, hypertensive, and nephrectomized animals. J. Exp. Med. 71, 495-519. doi: 10.1084/jem.71.4.495

Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A., Rawlik, K., Parkinson, N., et al. (2021). Genetic mechanisms of critical illness in Covid-19. Nature 591, 92-98. doi: 10.1038/s41586-020-03065-y

Patel, S. K., Velkoska, E., Freeman, M., Wai, B., Lancefield, T. F., and Burrell, L. M. (2014). From gene to protein - experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension. *Front. Physiol.* 5:227. doi: 10.3389/fphys.2014.00227

Patel, V. B., Zhong, J. C., Grant, M. B., and Oudit, G. Y. (2016). Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. *Circ. Res.* 118, 1313-1326. doi: 10.1161/CIRCRESAHA.116.307708

Patnaik, M., Pati, P., Swain, S. N., Mohapatra, M. K., Dwibedi, B., Kar, S. K., et al. (2014). Association of angiotensininconverting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha, India. Ann. Hum. Biol. 41, 145-152. doi: 10.3109/03014460.2013.837195

Paul, M., Poyan Mehr, A., and Kreutz, R. (2006). Physiology of local renin-angiotensin systems. *Physiol. Rev.* 86, 747-803. doi: 10.1152/physrev.00036.2005

Pedersen, K. B., Chhabra, K. H., Nguyen, V. K., Xia, H., and Lazartigues, E. (2013). The transcription factor HNF1alpha induces expression of angiotensin-converting enzyme 2 (ACE2) in pancreatic islets from evolutionarily conserved promoter motifs. *Biochim. Biophys. Acta* 1829, 1225-1235. doi: 10.1016/j.bbagrm.2013.09.007

Pena Silva, R. A., Chu, Y., Miller, J. D., Mitchell, I. J., Penninger, J. M., Faraci, F. M., et al. (2012). Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging. *Stroke* 43, 3358-3363. doi: 10.1161/STROKEAHA.112.667063

Peng, H., Li, W., Seth, D. M., Nair, A. R., Francis, J., and Feng, Y. (2013). (pro)renin receptor mediates both angiotensin II-dependent and-independent oxidative stress in neuronal cells. *PLoS One* 8:e58339. doi: 10.1371/journal.pone.0058339

Perlot, T., and Penninger, J. M. (2013). ACE2-from the renin-angiotensin system to gut microbiota and malnutrition. *Microbes Infect.* 15, 866-873. doi: 10.1016/j.micinf.2013.08.003

Phillips, M. I., and Schmidt-Ott, K. M. (1999). The discovery of renin 100 years ago. *News Physiol. Sci.* 14, 271-274. doi: 10.1152/physiologyonline.1999.14.6.271

Philogene, M. C., Johnson, T., Vaught, A. J., Zakaria, S., and Fedarko, N. (2019). Antibodies against angiotensin II type 1 and endothelin a receptors: relevance and pathogenicity. *Hum. Immunol.* 80, 561-567. doi: 10.1016/j.humimm.2019.04.012

Pierce, J. B., Simion, V., Icli, B., Perez-Cremades, D., Cheng, H. S., and Feinberg, M. W. (2020). Computational analysis of targeting SARS-CoV-2, viral entry proteins ACE2 and TMPRSS2, and interferon genes by host MicroRNAs. *Genes (Basel)* 11:1354. doi: 10.3390/genes1111354

Pinheiro, D. S., Santos, R. S., Jardim, P. C. B. V., Silva, E. G., Reis, A. A. S., Pedrino, G. R., et al. (2019). The combination of ACE I/D and ACE2 G8790A polymorphisms reveals susceptibility to hypertension: a genetic association study in Brazilian patients. *PLoS One* 14:e0221248. doi: 10.1371/journal.pone.0221248

Pinto, B. G. G., Oliveira, A. E. R., Singh, Y., Jimenez, L., Goncalves, A. N. A., Ogava, R. L. T., et al. (2020). ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19. *J. Infect. Dis.* 222, 556-563. doi: 10.1093/infdis/jiaa332

Pires de Souza, G. A., Osman, I. O., Le Bideau, M., Baudoin, J.-P., Jaafar, R., Devaux, C., et al. (2022). Angiotensin II receptor blockers (ARBs antihypertensive
agents) increase replication of SARS-CoV-2 in Vero E6 cells. *Front. Cell. Infect. Microbiol.* 11:639177. doi: 10.3389/fcimb.2021.639177

Poissy, J., Goutay, J., Caplan, M., Parmentier, E., Duburcq, T., Lassale, F., et al. (2020). Pulmonary embolism in patients with COVID19. *Circulation* 142, 184–186. doi: 10.1161/CIRCULATIONAHA.120.047430

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