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

Pouladi, N., and Abdolahi, S. (2021). Investigating the ACE2 polymorphisms in COVID-19 susceptibility: An in silico analysis. *Mol. Genet. Genom. Med.* 9:e1672. doi: 10.1002/mgg3.1672

Prajapat, M., Shekhar, N., Sarma, P., Avti, P., Singh, S., Kaur, H., et al. (2020). Virtual screening and molecular dynamics study of approved drugs as inhibitors of spike protein S1 domain and ACE2 interaction in SARS-CoV-2. *J. Mol. Graph. Model.* 101:107716. doi: 10.1016/j.jmgm.2020.107716

Prieto, M. C., Gonzalez-Villalobos, R. A., Botros, F. T., Martin, V. L., Pagan, J., Satou, R., et al. (2011). Reciprocal changes in renal ACE/ANG II and ACE2/ANG 1-7 are associated with enhanced collecting duct renin in Goldblatt hypertensive rats. *Am. J. Physiol. Ren. Physiol.* 300, F749–F755. doi: 10.1152/ajprenal.00383.2009

Procko, E. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2. bioRxiv [Preprint]. (2020). doi: 10.1101/2020.1103.1116.994236

Qaradakhi, T., and Gadanec, L. (2020). Could DIZE be the answer to COVID-19? *Maturitas* 140, 83–84. doi: 10.1016/j.maturitas.2020.07.002

Qi, Y. F., Zhang, J., Cole-Jeffrey, C. T., Shenoy, V., Espejo, A., Hanna, M., et al. (2013). Diminazene Aceturate enhances angiotensin-converting enzyme 2 activity and attenuates ischemia-induced cardiac pathophysiology. *Hypertension* 62, 746–752. doi: 10.1161/HYPERTENSIONAHA.113.01337

Qiao, Y., Wang, X. M., Mannan, R., Pitchiaya, S., Zhang, Y., Wotring, J. W., et al. (2021). Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2. *Proc. Natl. Acad. Sci. U. S. A.* 118:e2021450118. doi: 10.1073/pnas.2021450118

Qiu, Y., Shil, P. K., Zhu, P., Yang, H., Verma, A., Lei, B., et al. (2014). Angiotensin-converting enzyme 2 (ACE2) activator Diminazene Aceturate ameliorates endotoxin-induced uveitis in mice. *Invest. Ophthalmol. Vis. Sci.* 55, 3809–3818. doi: 10.1167/iovs.14-13883

Qiu, Y., Zhao, Y. B., Wang, Q., Li, J. Y., Zhou, Z. J., Liao, C. H., et al. (2020). Predicting the angiotensin converting enzyme 2 (ACE2) utilizing capability as the receptor of SARS-CoV-2. *Microbes Infect.* 22, 221–225. doi: 10.1016/j.micinf.2020.03.003

Radzikowska, U., Ding, M., Tan, G., Zhakparov, D., Peng, Y., Wawrzyniak, P., et al. (2020). Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. *Allergy* 75, 2829–2845. doi: 10.1111/all.14429

Raghavan, S., Kenchappa, D. B., and Leo, M. D. (2021). SARS-CoV-2 spike protein induces degradation of junctional proteins that maintain endothelial barrier integrity. *Front. Cardiovasc. Med.* 8:687783. doi: 10.3389/fcvm.2021.687783

Rajagopal, S., Rajagopal, K., and Lefkowitz, R. J. (2010). Teaching old receptors new tricks: biasing seven-transmembrane receptors. *Nat. Rev. Drug Discov.* 9, 373–386. doi: 10.1038/nrd3024

Reich, H. N., Oudit, G. Y., Penninger, J. M., Scholey, J. W., and Herzenberg, A. M. (2008). Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease. *Kidney Int.* 74, 1610–1616. doi: 10.1038/ki.2008.497

Reindl-Schwaighofer, R., Hödlmoser, S., Eskandary, F., Poglitsch, M., Bonderman, D., Strassl, R., et al. (2021). ACE2 elevation in severe COVID-19. *Am. J. Resp. Critic. Care Med.* 203, 1191–1196. doi: 10.1164/rccm.202101-0142LE

Ren, W., Lan, J., Ju, X., Gong, M., Long, Q., Zhu, Z., et al. (2021). Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption. *PLoS Pathog.* 17:e1010053. doi: 10.1371/journal.ppat.1010053

Rice, G. I., Jones, A. L., Grant, P. J., Carter, A. M., Turner, A. J., and Hooper, N. M. (2006). Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. *Hypertension* 48, 914–920. doi: 10.1161/01.HYP0000244543.91937.79

Rieder, M., Wirth, L., Pollmeier, L., Jeserich, M., Goller, I., Baldus, N., et al. (2021). Serum ACE2, angiotensin II, and aldosterone levels are unchanged in patients with COVID-19. *Am. J. Hypertens.* 34, 278–281. doi: 10.1093/ajh/hpa0169

Riordan, J. F. (2003). Angiotensin-I-converting enzyme and its relatives. *Genome Biol.* 4:225. doi: 10.1186/gb-2003-4-8-225

Rivière, G., Michaud, A., Corradi, H. R., Sturrock, E. D., Acharya, K. R., Coque, V., et al. (2007). Characterization of the first angiotensin-converting like enzyme in bacteria: ancestor ACE is already active. *Gene* 399, 81–91. doi: 10.1016/j.gene.2007.05.010

Robinson, F. A., Mihealsick, R. P., Wagener, B. M., Hanna, P., Poston, M. D., Efimov, I. R., et al. (2020). Role of angiotensin-converting enzyme 2 and pericytes

in cardiac complications of COVID-19 infection. *Am. J. Physiol. Heart Circ. Physiol.* 319, H1059–H1068. doi: 10.1152/ajpheart.00681.2020

Rodriguez Rodriguez, M., Castro Quismondo, N., Zafra Torres, D., Gil Alos, D., Ayala, R., and Martinez-Lopez, J. (2021). Increased von Willebrand factor antigen and low ADAMTS13 activity are related to poor prognosis in covid-19 patients. *Int. J. Lab. Hematol.* 43, O152–O155. doi: 10.1111/ijlh.13476

Rota, P. A., Oberste, M. S., Monroe, S. S., Nix, W. A., Campagnoli, R., Icenogle, J. P., et al. (2003). Characterization of a novel coronavirus associated with severe acute respiratory syndrome. *Science* 300, 1394–1399. doi: 10.1126/science.1085952

Rovas, A., Osiaevi, I., Buscher, K., Sackarnd, J., Tepasse, P. R., Fobker, M., et al. (2020). Microvascular dysfunction in COVID-19: the MYSTIC study. *Angiogenesis* 24, 145–157. doi: 10.1007/s10456-020-09753-7

Ruiz-Ortega, M., Lorenzo, O., Suzuki, Y., Rupe'rez, M., and Egido, J. (2001). Proinflammatory actions of angiotensins. *Curr. Opin. Nephrol. Hypertens.* 10, 321–329. doi: 10.1097/00041552-200105000-00005

Rushworth, C. A., Guy, J. L., and Turner, A. J. (2008). Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting enzymes (ACE and ACE2) identified by site-directed mutagenesis. *FEBS J.* 275, 6033–6042. doi: 10.1111/j.1742-4658.2008.06733.x

Rysz, S., Al-Saadi, J., Sjöström, A., Farm, M., Campoccia Jalde, F., Plattén, M., et al. (2021). COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system. *Nat. Commun.* 12:2417. doi: 10.1038/s41467-021-22713-z

Sadoshima, J., Qiu, Z. H., Morgan, J. P., and Izumo, S. (1995). Angiotensin-II and other hypertrophic stimuli mediated by G-protein-coupled receptors activate tyrosine kinase, mitogen-activated protein-kinase, and 90-Kd S6 kinase in cardiac myocytes - the critical role of Ca2+-dependent signaling. *Circ. Res.* 76, 1–15. doi: 10.1161/01.res.76.1.1

Sakka, M., Connors, J. M., He Kimian, G., Martin-Toutain, I., Crichi, B., Colmegna, I., et al. (2020). Association between D-dimer levels and mortality in patients with coronavirus disease 2019 COVID19: a systematic review and pooled analysis. *J. Med. Vasc.* 45, 268–274. doi: 10.1016/j.jdmv.2020.05.003

Sama, I. E., Ravera, A., Santema, B. T., van Goor, H., ter Maaten, J. M., Cleland, J. G. F., et al. (2020). Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. *Eur. Heart J.* 41, 1810–1817. doi: 10.1093/eurheartj/eha373

Samavati, L., and Uhal, B. D. (2020). ACE2, much more than just a receptor for SARS-COV-2. *Front. Cell. Infect. Microbiol.* 10:317. doi: 10.3389/fcimb.2020.00317

Santos, R. A. S., Sampaio, W. O., Alzamora, A. C., Motta-Santos, D., Alenina, N., Bader, M., et al. (2018). The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1-7). *Physiol. Rev.* 98, 505–553. doi: 10.1152/physrev.00023.2016

Santos, R. A., Silva AC, S. E., Maric, C., DMR, S., Machado, R. P., de Buhr, I., et al. (2003). Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. *Proc. Natl. Acad. Sci. U. S. A.* 100, 8258–8263. doi: 10.1073/pnas.1432869100

Sarzani, R., Giulietti, F., Di Pentima, C., Filipponi, A., and Spannella, F. (2020). Antagonizing the renin-angiotensin-aldosterone system in the era of COVID-19. *Intern. Emerg. Med.* 15, 885–887. doi: 10.1007/s11739-020-02365-5

Sato, T., Suzuki, T., Watanabe, H., Kadowaki, A., Fukamizu, A., Liu, P. P., et al. (2013). Apelin is a positive regulator of ACE2 in failing hearts. *J. Clin. Invest.* 123, 5203–5211. doi: 10.1172/JCI69608

Sayed-Tabatabaei, F. A., Oostra, B. A., Isaacs, A., van Duijn, C. M., and Witteman, J. C. M. (2006). ACE polymorphism. *Circ. Res.* 98, 1123–1133. doi: 10.1161/01.RES.0000223145.74217.e7

Schiffrin, E. L., Flack, J. M., Ito, S., Muntner, P., and Webb, R. C. (2020). Hypertension and COVID-19. *Am. J. Hypertens.* 33, 373–374. doi: 10.1093/ajh/hpa057

Schmidt, S., van Hooft, I. M., Grobbee, D. E., Ganten, D., and Ritz, E. (1993). Polymorphism of the angiotensin I converting enzyme gene is apparently not related to high blood pressure: Dutch hypertension and offspring study. *J. Hypertens.* 11, 345–348. doi: 10.1097/00004872-199304000-00003

Schmidt-Ott, K. M., Kagiyama, S., and Philips, M. I. (2000). The multiple actions of angiotensin II in atherosclerosis. *Regul. Pept.* 93, 65–77. doi: 10.1016/s0167-0115(00)00178-6

Schmieder, R. E., Hilgers, K. F., Schlaich, M. P., and Schmidt, B. M. W. (2007). Renin-angiotensin system and cardiovascular risk. *Lancet* 369, 1208–1219. doi: 10.1016/S0140-6736(07)60242-6

Sealey, J. E., and Rubattu, S. (1989). Prorenin and renin as separate mediators of tissue and circulating systems am. *J. Hypertens.* 2, 358–366. doi: 10.1093/ajh/2.5.358

Senchenkova, E. Y., Russell, J., Almeida-Paula, L. D., Harding, J. W., and Granger, D. N. (2010). Angiotensin II-mediated microvascular thrombosis. *Hypertension* 56, 1089–1095. doi: 10.1161/HYPERTENSIONAHA.110.15820
Senchenkova, E. Y., Russell, J., Esmon, C. T., and Granger, D. N. (2014). Roles of coagulation and fibrinolysis in angiotensin II enhanced microvascular thrombosis. *Microcirculation* 21, 401–407. doi: 10.1111/micc.12120

Shang, J., Ye, G., Shi, K., Wan, Y., Luo, C., Aihara, H., et al. (2020). Structural basis of receptor recognition by SARS-CoV-2. *Nature* 581, 221–224. doi: 10.1038/s41586-020-2179-y

Shen, L., Mo, H., Cai, L., Kong, T., Zheng, W., Ye, J., et al. (2009). Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases. *Shock* 31, 500–506. doi: 10.1097/SHK.0b013e318189017a

Shen, Q., Xiao, X., Aierken, A., Yue, W., Wu, X., Liao, M., et al. (2020). The ACE2 expression in Sertoli cells and germ cells may cause male reproductive disorder after SARS-CoV-2 infection. *J. Cell. Mol. Med.* 24, 9472–9477. doi: 10.1111/jcmm.15541

Shenoy, V., Gjymishka, A., Jarajapu, Y. P., Qi, Y., Afzal, A., Rigatto, K., et al. (2013). Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. *Am. J. Respir. Crit. Care Med.* 187, 648–657. doi: 10.1164/rccm.201205-0880OC

Sherman, E. J., and Emmer, B. T. (2021). ACE2 protein expression within isogenic cell lines is heterogeneous and associated with distinct transcriptomes. *Sci. Rep.* 11:15900. doi: 10.1038/s41598-021-95308-9

Shilts, J., Crozier, T. W. M., Greenwood, E. J. D., Lehner, P. J., and Wright, G. J. (2021). No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. *Sci. Rep.* 11:413. doi: 10.1038/s41598-020-80464-1

Shuai, H., Chan, J. F. W., Yuen, T. T. T., Yoon, C., Hu, J. C., Wen, L., et al. (2021). Emerging SARS-CoV-2 variants expand species tropism to murines. *eBioMed.* 73:103643. doi: 10.1016/j.ebiom.2021.103643

Shukla, N., Roelle, S. M., Suzart, V. G., Bruchez, A. M., and Matreyek, K. A. (2021). Mutants of human ACE2 differentially promote SARS-CoV and SARS-CoV-2 spike mediated infection. *PLoS Pathog.* 17:e1009715. doi: 10.1371/journal.ppat.1009715

Siddiquee, K., Hampton, J., McAnally, D., May, L., and Smith, L. (2013). The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. *Br. J. Pharmacol.* 168, 1104–1117. doi: 10.1111/j.1476-5381.2012.02192.x

Signature, V., Voicu, S., Neuwirth, M., Delrue, M., Gayat, E., Stépanian, A., et al. (2020). Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients? *Thromb. Res.* 195, 74–76. doi: 10.1016/j.thromres.2020.07.016

Silva, G. M., França-Falcão, M. S., Calzerra, N. T. M., Luz, M. S., Gadelha, D. D. A., Balarini, C. M., et al. (2020). Role of renin angiotensin system components in atherosclerosis: focus on Ang-II, ACE2, and Ang-1-7. *Front. Physiol.* 11:1067. doi: 10.3389/fphys.2020.01067

Simoes e Silva, A. C., Silveira, K. D., Ferreira, A. J., and Teixeira, M. M. (2013). ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. *Br. J. Pharmacol.* 169, 477–492. doi: 10.1111/bph.12159

Singer, D., and Camargo, S. M. R. (2011). Collectrin and ACE2 in renal and intestinal amino acid transport. *Channels* 5, 410–423. doi: 10.4161/chan.5.5.16470

Singer, D., Camargo, S. M. R., Ramadam, T., Schäfer, M., Mariotta, L., Herzog, B., et al. (2012). Defective intestinal amino acid absorption in ACE2 null mice. *Am. J. Physiol. Gastrointest. Liver Physiol.* 303, G686–G695. doi: 10.1152/ajpgi.00140.2012

Singh, K. D., and Karnik, S. S. (2016). Angiotensin receptors: structure, function, signaling and clinical applications. *J. Cell Signal.* 1:111. doi: 10.4172/jcs.1000111

Skeggs, L. T. Jr., Kahn, J. R., and Shumway, N. P. (1956). The preparation and function of the hypertensin-converting enzyme. *J. Exp. Med.* 103, 295–299. doi: 10.1084/jem.103.3.295

Skidgel, R. A., and Erdos, E. G. (1987). The broad substrate specificity of human angiotensin I converting enzyme. *Clin. Exp. Hypertens.* A 9, 243–259. doi: 10.3109/10641968709164184

Smadja, D. M., Mentzer, S., Fontenay, M., Laffan, M. A., Ackermann, M., Helms, J., et al. (2021). COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects. *Angiogenesis* 24, 755–788. doi: 10.1007/s10456-021-09805-6

Sodhi, C. P., Wohlford-Lenane, C., Yamaguchi, Y., Prindle, T., Fulton, W. B., Wang, S., et al. (2017). Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. *AJP Lung Cell. Mol. Physiol.* 314, L17–L31. doi: 10.1152/apjlung.00498.2016

Sorokina, M., Teixeira, J. M. C., Barrera-Vilarmau, S., Paschkle, R., Papasotiriou, I., Rodrigues, J. P. L. M., et al. (2020). Structural models of human ACE2 variants with SARS-CoV-2 spike protein for structure-based drug design. *Sci. Data* 7:309. doi: 10.1038/s41597-020-00652-6

Spitler, K. M., and Webb, R. C. (2014). Endoplasmic reticulum stress contributes to aortic stiffening via proapoptotic and fibrotic signaling mechanisms. *Hypertension* 63, e40–e45. doi: 10.1161/HYPERTENSIONAHA.113.02558

Stawiski, EW, Diwanji, D, Suryamohan, K, Gupta, R., Fellouse, FA, Sathirapongkasuti, JF, et al. Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility. *bioRxiv* [Preprint] (2020). doi: 10.1101/2020.04.07.024752

Stefely, J. A., Christensen, B. B., Gogakos, T., Conne Sullivan, J. K., Montgomery, G. G., Barranco, J. P., et al. (2020). Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. *Am. J. Hematol.* 95, 1522–1530. doi: 10.1002/ajh.25979

Strafella, C., Caputo, V., Termine, A., Barati, S., Caltagirone, C., Giardina, E., et al. (2020). Investigation of genetic variations of IL6 and IL6r as potential prognostic and pharmacogenetics biomarkers: implications for covid-19 and neuroinflammatory disorders. *Lifestyles* 10, 1–10. doi: 10.3390/life10120351

Suryamohan, K., Diwanji, D., Stawiski, E. W., Gupta, R., Miersch, S., Liu, J., et al. (2021). Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2. *Comm. Biol.* 4:475. doi: 10.1038/s42003-021-02030-3

Takayanagi, T., Kawai, T., Forrester, S. J., Obama, T., Tsuchi, T., Fukuda, Y., et al. (2015). Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II. *Hypertension* 65, 1349–1355. doi: 10.1161/HYPERTENSIONAHA.115.03544

Tan, Y. K., Goh, C., Leow, A. S. T., Tambyah, P. A., Ang, A., Yap, E. S., et al. (2020). COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature. *J. Thromb. Thrombolysis* 50, 587–595. doi: 10.1007/s11239-020-02228-y

Tang, T., Bidon, M., Jaimes, J. A., Whittaker, G. R., and Daniel, S. (2020). Coronavirus membrane fusion mechanism offers a potential target for antiviral development. *Antivir. Res.* 178:104792. doi: 10.1016/j.antiviral.2020.104792

Tay, M. Z., Poh, C. M., Renia, L., MacAry, P. A., and Ng, L. F. P. (2020). The trinity of COVID19: immunity, inflammation and intervention. *Nat. Rev. Immunol.* 20, 363–374. doi: 10.1038/s41577-020-0311-8

Tereshchenko, L. G., Johnson, K., Khayyat-Kholghi, M., and Johnson, B. (2022). Rate of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers use and the number of COVID-19-confirmed cases and deaths. *Am. J. Cardiol.* 165, 101–108. doi: 10.1016/j.amjcard.2021.10.050

Thomas, M. C., Pickering, R. J., Tsorotes, D., Koitka, A., Sheehy, K., Bernardi, S., et al. (2010). Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse. *Circ. Res.* 107, 888–897. doi: 10.1161/CIRCRESAHA.110.219279

Tigerstedt, R., and Bergman, P. G. (1898). Niere und kreislauf. *Skand. Arch. Physiol.* 8, 223–271. doi: 10.1111/j.1748-1716.1898.tb00272.x

Tignarelli, C. J., Ingraham, N. E., Sparks, M. A., Reilkoff, R., Bezdicek, T., Benson, B., et al. (2020). Antihypertensive drugs and risk of COVID-19? *Lancet Respir. Med.* 8, e30–e31. doi: 10.1016/S2213-2600(20)30153-3

Tikellis, C., Pickering, R., Tsorotes, D., Du, X. J., Kiriazis, H., Nguyen-Huu, T. P., et al. (2012). Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes. *Clin. Sci. (Lond.)* 123, 519–529. doi: 10.1042/CS20110668

Tikellis, C., and Thomas, M. C. (2012). Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. *Int. J. Pept. Actions* 2012:256294. doi: 10.1155/2012/256294

Tipnis, S. R., Hooper, N. M., and Hyde, R. (2000). A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. *J. Biol. Chem.* 275, 33238–33243. doi: 10.1074/jbc.M002615200

Tong, M., Jiang, Y., Xia, D., Xiong, Y., Zheng, Q., Chen, F., et al. (2020). Elevated serum endothelial cell adhesion molecules expression in COVID-19 patients. *J. Infect. Dis.* 222, 894–898. doi: 10.1093/infdis/jia349

Towler, P., Staker, B., Prasad, S. G., Menon, S., Tang, J., Parsons, T., et al. (2004). ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. *J. Biol. Chem.* 279, 17996–18007. doi: 10.1074/jbc.M311191200

Tukiainen, T., Villani, A. C., Yen, A., Rivas, M. A., Marshall, J. L., Satija, R., et al. (2017). Landscape of X chromosome inactivation across human tissues. *Nature* 550, 244–248. doi: 10.1038/nature24265

Turner, A. J., and Hooper, N. M. (2002). The angiotensin-converting enzyme gene family: genomics and pharmacology. *Trends Pharmacol. Sci.* 23, 177–183. doi: 10.1016/s0165-6147(00)01994-5

Ueda, S., Elliott, H. L., Morton, J. J., and Connell, J. M. (1995). Enhanced pressor response to angiotensin I in normotensive men with the deletion genotype (DD) for angiotensin-converting enzyme. *Hypertension* 25, 1266–1269. doi: 10.1161/01.hyp.25.6.1266

Uijl, E., Mirabito Colafella, K. M., Sun, Y., Ren, L., van Veghel, R., Garrelds, I. M., et al. (2019). Strong and sustained antihypertensive effect of small interfering RNA targeting liver angiotensinogen. *Hypertension* 73, 1249–1257. doi: 10.1161/HYPERTENSIONAHA.119.12703

Vaduganathan, M., Varden, O., Michel, T., McMurray, J. J. V., Pfeffer, M. A., and Solomon, S. D. (2020). Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19. *N. Engl. J. Med.* 382, 1653–1659. doi: 10.1056/NEJMsr2005760
Senchenkova, E. Y., Russell, J., Esmon, C. T., and Granger, D. N. (2014). Roles of coagulation and fibrinolysis in angiotensin II enhanced microvascular thrombosis. *Microcirculation* 21, 401–407. doi: 10.1111/micc.12120

Shang, J., Ye, G., Shi, K., Wan, Y., Luo, C., Aihara, H., et al. (2020). Structural basis of receptor recognition by SARS-CoV-2. *Nature* 581, 221–224. doi: 10.1038/s41586-020-2179-y

Shen, L., Mo, H., Cai, L., Kong, T., Zheng, W., Ye, J., et al. (2009). Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases. *Shock* 31, 500–506. doi: 10.1097/SHK.0b013e318189017a

Shen, Q., Xiao, X., Aierken, A., Yue, W., Wu, X., Liao, M., et al. (2020). The ACE2 expression in Sertoli cells and germ cells may cause male reproductive disorder after SARS-CoV-2 infection. *J. Cell. Mol. Med.* 24, 9472–9477. doi: 10.1111/jcmm.15541

Shenoy, V., Gjymishka, A., Jarajapu, Y. P., Qi, Y., Afzal, A., Rigatto, K., et al. (2013). Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. *Am. J. Respir. Crit. Care Med.* 187, 648–657. doi: 10.1164/rccm.201205-0880OC

Sherman, E. J., and Emmer, B. T. (2021). ACE2 protein expression within isogenic cell lines is heterogeneous and associated with distinct transcriptomes. *Sci. Rep.* 11:15900. doi: 10.1038/s41598-021-95308-9

Shilts, J., Crozier, T. W. M., Greenwood, E. J. D., Lehner, P. J., and Wright, G. J. (2021). No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. *Sci. Rep.* 11:413. doi: 10.1038/s41598-020-80464-1

Shuai, H., Chan, J. F. W., Yuen, T. T. T., Yoon, C., Hu, J. C., Wen, L., et al. (2021). Emerging SARS-CoV-2 variants expand species tropism to murines. *eBioMed.* 73:103643. doi: 10.1016/j.ebiom.2021.103643

Shukla, N., Roelle, S. M., Suzart, V. G., Bruchez, A. M., and Matreyek, K. A. (2021). Mutants of human ACE2 differentially promote SARS-CoV and SARS-CoV-2 spike mediated infection. *PLoS Pathog.* 17:e1009715. doi: 10.1371/journal.ppat.1009715

Siddiquee, K., Hampton, J., McAnally, D., May, L., and Smith, L. (2013). The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. *Br. J. Pharmacol.* 168, 1104–1117. doi: 10.1111/j.1476-5381.2012.02192.x

Signature, V., Voicu, S., Neuwirth, M., Delrue, M., Gayat, E., Stépanian, A., et al. (2020). Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients? *Thromb. Res.* 195, 74–76. doi: 10.1016/j.thromres.2020.07.016

Silva, G. M., França-Falcão, M. S., Calzerra, N. T. M., Luz, M. S., Gadelha, D. D. A., Balarini, C. M., et al. (2020). Role of renin angiotensin system components in atherosclerosis: focus on Ang-II, ACE2, and Ang-1-7. *Front. Physiol.* 11:1067. doi: 10.3389/fphys.2020.01067

Simoes e Silva, A. C., Silveira, K. D., Ferreira, A. J., and Teixeira, M. M. (2013). ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. *Br. J. Pharmacol.* 169, 477–492. doi: 10.1111/bph.12159

Singer, D., and Camargo, S. M. R. (2011). Collectrin and ACE2 in renal and intestinal amino acid transport. *Channels* 5, 410–423. doi: 10.4161/chan.5.5.16470

Singer, D., Camargo, S. M. R., Ramadam, T., Schäfer, M., Mariotta, L., Herzog, B., et al. (2012). Defective intestinal amino acid absorption in ACE2 null mice. *Am. J. Physiol. Gastrointest. Liver Physiol.* 303, G686–G695. doi: 10.1152/ajpgi.00140.2012

Singh, K. D., and Karnik, S. S. (2016). Angiotensin receptors: structure, function, signaling and clinical applications. *J. Cell Signal.* 1:111. doi: 10.4172/jcs.1000111

Skeggs, L. T. Jr., Kahn, J. R., and Shumway, N. P. (1956). The preparation and function of the hypertensin-converting enzyme. *J. Exp. Med.* 103, 295–299. doi: 10.1084/jem.103.3.295

Skidgel, R. A., and Erdos, E. G. (1987). The broad substrate specificity of human angiotensin I converting enzyme. *Clin. Exp. Hypertens.* A 9, 243–259. doi: 10.3109/10641968709164184

Smadja, D. M., Mentzer, S., Fontenay, M., Laffan, M. A., Ackermann, M., Helms, J., et al. (2021). COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects. *Angiogenesis* 24, 755–788. doi: 10.1007/s10456-021-09805-6

Sodhi, C. P., Wohlford-Lenane, C., Yamaguchi, Y., Prindle, T., Fulton, W. B., Wang, S., et al. (2017). Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. *AJP Lung Cell. Mol. Physiol.* 314, L17–L31. doi: 10.1152/apjlung.00498.2016

Sorokina, M., Teixeira, J. M. C., Barrera-Vilarmau, S., Paschkle, R., Papasotiriou, I., Rodrigues, J. P. L. M., et al. (2020). Structural models of human ACE2 variants with SARS-CoV-2 spike protein for structure-based drug design. *Sci. Data* 7:309. doi: 10.1038/s41597-020-00652-6

Spitler, K. M., and Webb, R. C. (2014). Endoplasmic reticulum stress contributes to aortic stiffening via proapoptotic and fibrotic signaling mechanisms. *Hypertension* 63, e40–e45. doi: 10.1161/HYPERTENSIONAHA.113.02558

Stawiski, EW, Diwanji, D, Suryamohan, K, Gupta, R., Fellouse, FA, Sathirapongkasuti, JF, et al. Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility. *bioRxiv* [Preprint] (2020). doi: 10.1101/2020.04.07.024752

Stefely, J. A., Christensen, B. B., Gogakos, T., Conne Sullivan, J. K., Montgomery, G. G., Barranco, J. P., et al. (2020). Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. *Am. J. Hematol.* 95, 1522–1530. doi: 10.1002/ajh.25979

Strafella, C., Caputo, V., Termine, A., Barati, S., Caltagirone, C., Giardina, E., et al. (2020). Investigation of genetic variations of IL6 and IL6r as potential prognostic and pharmacogenetics biomarkers: implications for covid-19 and neuroinflammatory disorders. *Lifestyles* 10, 1–10. doi: 10.3390/life10120351

Suryamohan, K., Diwanji, D., Stawiski, E. W., Gupta, R., Miersch, S., Liu, J., et al. (2021). Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2. *Comm. Biol.* 4:475. doi: 10.1038/s42003-021-02030-3

Takayanagi, T., Kawai, T., Forrester, S. J., Obama, T., Tsuchi, T., Fukuda, Y., et al. (2015). Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II. *Hypertension* 65, 1349–1355. doi: 10.1161/HYPERTENSIONAHA.115.03544

Tan, Y. K., Goh, C., Leow, A. S. T., Tambyah, P. A., Ang, A., Yap, E. S., et al. (2020). COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature. *J. Thromb. Thrombolysis* 50, 587–595. doi: 10.1007/s11239-020-02228-y

Tang, T., Bidon, M., Jaimes, J. A., Whittaker, G. R., and Daniel, S. (2020). Coronavirus membrane fusion mechanism offers a potential target for antiviral development. *Antivir. Res.* 178:104792. doi: 10.1016/j.antiviral.2020.104792

Tay, M. Z., Poh, C. M., Renia, L., MacAry, P. A., and Ng, L. F. P. (2020). The trinity of COVID19: immunity, inflammation and intervention. *Nat. Rev. Immunol.* 20, 363–374. doi: 10.1038/s41577-020-0311-8

Tereshchenko, L. G., Johnson, K., Khayyat-Kholghi, M., and Johnson, B. (2022). Rate of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers use and the number of COVID-19-confirmed cases and deaths. *Am. J. Cardiol.* 165, 101–108. doi: 10.1016/j.amjcard.2021.10.050

Thomas, M. C., Pickering, R. J., Tsorotes, D., Koitka, A., Sheehy, K., Bernardi, S., et al. (2010). Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse. *Circ. Res.* 107, 888–897. doi: 10.1161/CIRCRESAHA.110.219279

Tigerstedt, R., and Bergman, P. G. (1898). Niere und kreislauf. *Skand. Arch. Physiol.* 8, 223–271. doi: 10.1111/j.1748-1716.1898.tb00272.x

Tignarelli, C. J., Ingraham, N. E., Sparks, M. A., Reilkoff, R., Bezdicek, T., Benson, B., et al. (2020). Antihypertensive drugs and risk of COVID-19? *Lancet Respir. Med.* 8, e30–e31. doi: 10.1016/S2213-2600(20)30153-3

Tikellis, C., Pickering, R., Tsorotes, D., Du, X. J., Kiriazis, H., Nguyen-Huu, T. P., et al. (2012). Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes. *Clin. Sci. (Lond.)* 123, 519–529. doi: 10.1042/CS20110668

Tikellis, C., and Thomas, M. C. (2012). Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. *Int. J. Pept. Actions* 2012:256294. doi: 10.1155/2012/256294

Tipnis, S. R., Hooper, N. M., and Hyde, R. (2000). A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. *J. Biol. Chem.* 275, 33238–33243. doi: 10.1074/jbc.M002615200

Tong, M., Jiang, Y., Xia, D., Xiong, Y., Zheng, Q., Chen, F., et al. (2020). Elevated serum endothelial cell adhesion molecules expression in COVID-19 patients. *J. Infect. Dis.* 222, 894–898. doi: 10.1093/infdis/jia349

Towler, P., Staker, B., Prasad, S. G., Menon, S., Tang, J., Parsons, T., et al. (2004). ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. *J. Biol. Chem.* 279, 17996–18007. doi: 10.1074/jbc.M311191200

Tukiainen, T., Villani, A. C., Yen, A., Rivas, M. A., Marshall, J. L., Satija, R., et al. (2017). Landscape of X chromosome inactivation across human tissues. *Nature* 550, 244–248. doi: 10.1038/nature24265

Turner, A. J., and Hooper, N. M. (2002). The angiotensin-converting enzyme gene family: genomics and pharmacology. *Trends Pharmacol. Sci.* 23, 177–183. doi: 10.1016/s0165-6147(00)01994-5

Ueda, S., Elliott, H. L., Morton, J. J., and Connell, J. M. (1995). Enhanced pressor response to angiotensin I in normotensive men with the deletion genotype (DD) for angiotensin-converting enzyme. *Hypertension* 25, 1266–1269. doi: 10.1161/01.hyp.25.6.1266

Uijl, E., Mirabito Colafella, K. M., Sun, Y., Ren, L., van Veghel, R., Garrelds, I. M., et al. (2019). Strong and sustained antihypertensive effect of small interfering RNA targeting liver angiotensinogen. *Hypertension* 73, 1249–1257. doi: 10.1161/HYPERTENSIONAHA.119.12703

Vaduganathan, M., Varden, O., Michel, T., McMurray, J. J. V., Pfeffer, M. A., and Solomon, S. D. (2020). Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19. *N. Engl. J. Med.* 382, 1653–1659. doi: 10.1056/NEJMsr2005760
Vandestienne, M., Zhang, Y., Santos-Zas, I., Al-Rifai, R., Joffre, J., Giraud, A., et al. (2021). TREM-1 orchestrates angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm. *J. Clin. Invest.* 131:e142468. doi: 10.1172/JCI142468

Varanat, M., Haase, E. M., Kay, J. G., and Scannapieco, F. A. (2017). Activation of the TREM-1 pathway in human monocytes by periodontal pathogens and oral commensal bacteria. *Mol Oral Microbiol* 32, 257–287. doi: 10.1111/omi.12169

Vassiliou, A. G., Keskinidou, C., Jahaj, E., Gallos, P., Dimopoulou, I., Kotanidou, A., et al. (2021). ICU admission levels of endothelial biomarkers as predictors of mortality in critically ill COVID-19 patients. *Cells* 10:186. doi: 10.3390/cells10010186

Velkoska, E., Patel, S. K., and Burrell, L. M. (2016). Angiotensin converting enzyme 2 and diminazene: role in cardiovascular and blood pressure regulation. *Curr. Opin. Nephrol. Hypertens.* 25, 384–395. doi: 10.1097/MNH.0000000000000254

Velloso, L. A., Folli, F., Sun, X. J., White, M. F., Saad, M. J. A., and Kahn, C. R. (1996). Cross-talk between the insulin and angiotensin signaling systems. *Proc. Natl. Acad. Sci. U. S. A.* 93, 12490–12495. doi: 10.1073/pnas.93.22.12490

Verdecchia, P., Angeli, F., Mazzotta, G., Gentile, G., and Reboldi, G. (2008). The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. *Vasc. Health Risk Manag.* 4, 971–981. doi: 10.2147/vhrm.s3215

Verdecchia, P., Cavallini, C., Spanevello, A., and Angeli, F. (2020). The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. *Eur. J. Intern. Med.* 76, 14–20. doi: 10.1016/j.ejim.2020.04.037

Verma, S., Abbas, M., Verma, S., Khan, F. H., Raza, S. T., Siddigi, Z., et al. (2021). Impact of I/D polymorphism of angiotensin-converting enzyme 1 (ACE1) gene on the severity of COVID-19 patients. *Infect. Genet. Evol.* 91:104801. doi: 10.1016/j.meegid.2021.104801

Verma, A., Xu, K., Du, T., Zhu, P., Liang, Z., Liao, S., et al. (2019). Expression of human ACE2 in lactobacillus and beneficial effects in diabetic retinopathy in mice. *Mol. Ther. Methods Clin. Dev.* 14, 161–170. doi: 10.1016/j.omtm.2019.06.007

Vicenzi, M., Di Cosola, R., Ruscica, M., Ratti, A., Rota, I., Rota, F., et al. (2020). The liaison between respiratory failure and high blood pressure: evidence from COVID-19 patients. *Eur. Respir. J.* 56:2001157. doi: 10.1183/13993003.01157-2020

Vickers, C., Hales, P., Kaushik, V., Dick, L., Gavin, J., Tang, J., et al. (2002). Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. *J. Biol. Chem.* 277, 14838–14843. doi: 10.1074/jbc.M200581200

Vitte, J., Diallo, A. B., Boumaza, A., Lopez, A., Michel, M., Allardet-Servent, J., et al. (2020). A granulocytic signature identifies COVID-19 and its severity. *J. Infect. Dis.* 222, 1985–1996. doi: 10.1093/infdis/jiaa591

Vuille-Dit-Bille, R. N., Camargo, S. M., Emmenegger, L., Sasse, T., Kummer, E., Jando, J., et al. (2015). Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. *Amino Acids* 47, 693–705. doi: 10.1007/s00726-014-1889-6

Wacharpluesadee, S., Tan, C. W., Maneeorn, P., Duengkae, P., Zhu, F., Joyjinda, Y., et al. (2021). Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in Southeast Asia. *Nat. Commun.* 12:972. doi: 10.1038/s41467-021-21240-1

Wakahara, S., Konoshita, T., Mizuno, S., Motomura, M., Aoyama, C., Makino, Y., et al. (2007). Synergistic expression of angiotensin-converting enzyme (ACE) and ACE2 in human renal tissue and confounding effects of hypertension on the ACE to ACE2 ratio. *Endocrinology* 148, 2453–2457. doi: 10.1210/en.2006-1287

Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T., and Veesler, D. (2020). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. *Cells* 181, 281–292. doi: 10.1016/j.cell.2020.02.058

Wang, K., Chen, W., Zhang, Z., Deng, Y., Lian, J. Q., Peng, D., et al. (2020). CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. *Signal Transduct. Target. Ther.* 5:283. doi: 10.1038/s41392-020-00426-x

Wang, H., Ji, Y., Wu, G., Sun, K., Sun, Y., Li, W., et al. (2015). L-tryptophan activates mammalian target of rapamycin and enhances expression of tight junction proteins in intestinal porcine epithelial cells. *J. Nutr.* 145, 1156–1162. doi: 10.3945/jn.114.209817

Wang, C., Jin, R., Zhu, X., Yan, J., and Li, G. (2015). Function of CD147 in atherosclerosis and atherothrombosis. *J. Cardiovasc. Transl. Res.* 8, 59–66. doi: 10.1007/s12265-015-9608-6

Wang, F., Lu, X., Peng, K., Zhou, L., Li, C., Wang, W., et al. (2014). COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla. *Am. J. Physiol. Ren. Physiol.* 307, F25–F32. doi: 10.1152/ajprenal.00548.2013

Wang, W., Luo, L., Lu, H., Chen, S., Kang, L., and Cui, F. (2015). Angiotensin-converting enzymes modulate aphid-plant interactions. *Sci. Rep.* 5:8885. doi: 10.1038/srep08885

Wang, C., Wang, S., Li, D., Wei, D. Q., Zhao, J., and Wang, J. (2020). Human intestinal defensin 5 inhibits SARS-CoV-2 invasion by cloaking ACE2. *Gastroenterology* 159, 1145–1147.e4. doi: 10.1053/j.gastro.2020.05.015

Wang, Q., Zhang, Y., Wu, L., Niu, S., Song, C., Zhang, Z., et al. (2020). Structural and functional basis of SARS-CoV-2 entry by using human ACE2. *Cells* 181, 894–904.e9. doi: 10.1016/j.cell.2020.03.045

Wang, M. Y., Zhao, R., Gao, L. J., Gao, X. F., Wang, D. P., and Cao, J. M. (2020). SARS-CoV-2: structure, biology, and structure-based therapeutics development. *Front. Cell. Infect. Microbiol.* 10:587269. doi: 10.3389/fcimb.2020.587269

Watanabe, T., Barker, T. A., and Berk, B. C. (2005). Angiotensin II and the endothelium: diverse signals and effects. *Hypertension* 45, 163–169. doi: 10.1161/01.HYP.0000153321.13792.b9

Wei, C., Shan, K. J., Wang, W., Zhang, S., Huan, Q., and Qian, W. (2021). Evidence for a mouse origin of the SARS-CoV-2 omicron variant. *J. Genet. Genom.* 48, 1111–1121. doi: 10.1016/j.jgg.2021.12.003

Wenzel, J., Lampe, J., Müller-Fielitz, H., Schuster, R., Zille, M., Müller, K., et al. (2021). The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. *Nat. Neurosci.* 24, 1522–1533. doi: 10.1038/s41593-021-00926-1

Wicik, Z., Eyileten, C., Jakubik, D., Simoes, S. N., Martins, D. C. Jr., Pavao, R., et al. (2020). ACE2 interaction networks in COVID-19: a physiological framework for prediction of outcome in patients with cardiovascular risk factors. *J. Clin. Med.* 9:3743. doi: 10.3390/jcm9113743

Wright, J. M. (2000). Choosing a first-line drug in the management of elevated blood pressure: what is the evidence? 3: angiotensin-converting-enzyme inhibitors. *AJC* 163, 293–296.

Wu, Y.-H., Li, J.-Y., Wang, C., Zhang, L.-M., and Qiao, H. (2017). The ACE2 G8790A polymorphism: involvement in type 2 diabetes mellitus combined with cerebral stroke. *J. Clin. Lab. Anal.* 31:e22033. doi: 10.1002/jla.22033

Wysocki, J., Garcia-Halpin, L., Ye, M., Maier, C., Sowers, K., Burns, K. D., et al. (2013). Regulation of urinary ACE2 in diabetic mice. *Am. J. Physiol. Physiol.* 305, F600–F611. doi: 10.1152/ajprenal.00600.2012

Xiao, M., Zhang, Y., Zhang, S., Qin, X., Xia, P., Cao, W., et al. (2020). Antiphospholipid antibodies in critically ill patients with coronavirus disease 2019 (COVID-19). *Arthritis Rheum.* 72, 1998–2004. doi: 10.1002/art.41425

Xiao, F., Zimpelmann, J., Agaybi, S., Gurley, S. B., Puente, L., and Burns, K. D. (2014). Characterization of angiotensin-converting enzyme 2 ectodomain shedding from mouse proximal tubular cells. *PLoS One* 9:e85958. doi: 10.1371/journal.pone.0085958

Xie, X., Chen, J., Wang, X., Zhang, F., and Liu, Y. (2006). Age-and genderrelated difference of ACE2 expression in rat lung. *Life Sci.* 78, 2166–2171. doi: 10.1016/j.lfs.2005.09.038

Xie, Y., Xu, E., Bowe, B., and Al-Aly, Z. (2022). Long-term cardiovascular outcomes of COVID-19. *Nat. Med.* 28, 583–590. doi: 10.1038/s41591-022-01689-3

Xu, Q., Jensen, D. D., Peng, H., and Feng, Y. (2016). The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure. *Pharmacol. Ther.* 164, 126–134. doi: 10.1016/j.pharmthera.2016.04.006

Xu, Y., and Li, Y. (2021). MicroRNA-28-3p inhibits angiotensin-converting enzyme 2 ectodomain shedding in 293T cells treated with the spike protein of severe acute respiratory syndrome coronavirus 2 by targeting a disintegrin and metalloproteinase 17. *Int. J. Mol. Med.* 48:189. doi: 10.3892/ijmm.2021.5022

Xu, C., Wang, A., Marin, M., Honnen, W., Ramasamy, S., Porter, E., et al. (2021). Human Defensins inhibit SARS-CoV-2 infection by blocking viral entry. *Viruses* 13:1246. doi: 10.3390/v13071246

Xu, H., Zhong, L., Deng, J., Peng, J., Dan, H., Zeng, X., et al. (2020). High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. *Int. J. Oral Sci.* 12-8. doi: 10.1038/s41368-020-0074-x

Xue, B., Zhang, Z., Roncari, C. F., Guo, F., and Johnson, A. K. (2012). Aldosterone acting through the central nervous system sensitizes angiotensin II-induced hypertension. *Hypertension* 60, 1023–1030. doi: 10.1161/HYPERTENSIONAHA.112.196576

Yamamoto, N., Nishida, N., Yamamoto, R., Gojobori, T., Shimotohno, K., Mizokami, M., et al. (2021). Angiotensin-converting enzyme (ACE) 1 gene polymorphism and phenotypic expression of COVID-19 symptoms. *Gene* 12:1572. doi: 10.3390/genes12101572

Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., Zhou, Q., et al. (2020). Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. *Science* 367, 1444–1448. doi: 10.1126/science.abb2762

Yang, J. M., Dong, M., Meng, X., Zhao, Y. X., Yang, X. Y., Liu, X. L., et al. (2013). Angiotensin-(1-7) dose-dependently inhibits atherosclerotic lesion formation and enhances plaque stability by targeting vascular cells. *Arteriosc. Thromb. Vascular Biol.* 33, 1978–1985. doi: 10.1161/ATVBAHA.113.301320

Yang, P., Gu, H., Zhao, Z., Wang, W., Cao, B., Lai, C., et al. (2014). Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. *Sci. Rep.* 4:7027. doi: 10.1038/srep07027
Vandestienne, M., Zhang, Y., Santos-Zas, I., Al-Rifai, R., Joffre, J., Giraud, A., et al. (2021). TREM-1 orchestrates angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm. *J. Clin. Invest.* 131:e142468. doi: 10.1172/JCI142468

Varanat, M., Haase, E. M., Kay, J. G., and Scannapieco, F. A. (2017). Activation of the TREM-1 pathway in human monocytes by periodontal pathogens and oral commensal bacteria. *Mol Oral Microbiol* 32, 257–287. doi: 10.1111/omi.12169

Vassiliou, A. G., Keskinidou, C., Jahaj, E., Gallos, P., Dimopoulou, I., Kotanidou, A., et al. (2021). ICU admission levels of endothelial biomarkers as predictors of mortality in critically ill COVID-19 patients. *Cells* 10:186. doi: 10.3390/cells10010186

Velkoska, E., Patel, S. K., and Burrell, L. M. (2016). Angiotensin converting enzyme 2 and diminazene: role in cardiovascular and blood pressure regulation. *Curr. Opin. Nephrol. Hypertens.* 25, 384–395. doi: 10.1097/MNH.0000000000000254

Velloso, L. A., Folli, F., Sun, X. J., White, M. F., Saad, M. J. A., and Kahn, C. R. (1996). Cross-talk between the insulin and angiotensin signaling systems. *Proc. Natl. Acad. Sci. U. S. A.* 93, 12490–12495. doi: 10.1073/pnas.93.22.12490

Verdecchia, P., Angeli, F., Mazzotta, G., Gentile, G., and Reboldi, G. (2008). The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. *Vasc. Health Risk Manag.* 4, 971–981. doi: 10.2147/vhrm.s3215

Verdecchia, P., Cavallini, C., Spanevello, A., and Angeli, F. (2020). The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. *Eur. J. Intern. Med.* 76, 14–20. doi: 10.1016/j.ejim.2020.04.037

Verma, S., Abbas, M., Verma, S., Khan, F. H., Raza, S. T., Siddigi, Z., et al. (2021). Impact of I/D polymorphism of angiotensin-converting enzyme 1 (ACE1) gene on the severity of COVID-19 patients. *Infect. Genet. Evol.* 91:104801. doi: 10.1016/j.meegid.2021.104801

Verma, A., Xu, K., Du, T., Zhu, P., Liang, Z., Liao, S., et al. (2019). Expression of human ACE2 in lactobacillus and beneficial effects in diabetic retinopathy in mice. *Mol. Ther. Methods Clin. Dev.* 14, 161–170. doi: 10.1016/j.omtm.2019.06.007

Vicenzi, M., Di Cosola, R., Ruscica, M., Ratti, A., Rota, I., Rota, F., et al. (2020). The liaison between respiratory failure and high blood pressure: evidence from COVID-19 patients. *Eur. Respir. J.* 56:2001157. doi: 10.1183/13993003.01157-2020

Vickers, C., Hales, P., Kaushik, V., Dick, L., Gavin, J., Tang, J., et al. (2002). Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. *J. Biol. Chem.* 277, 14838–14843. doi: 10.1074/jbc.M200581200

Vitte, J., Diallo, A. B., Boumaza, A., Lopez, A., Michel, M., Allardet-Servent, J., et al. (2020). A granulocytic signature identifies COVID-19 and its severity. *J. Infect. Dis.* 222, 1985–1996. doi: 10.1093/infdis/jiaa591

Vuille-Dit-Bille, R. N., Camargo, S. M., Emmenegger, L., Sasse, T., Kummer, E., Jando, J., et al. (2015). Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. *Amino Acids* 47, 693–705. doi: 10.1007/s00726-014-1889-6

Wacharpluesadee, S., Tan, C. W., Maneeorn, P., Duengkae, P., Zhu, F., Joyjinda, Y., et al. (2021). Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in Southeast Asia. *Nat. Commun.* 12:972. doi: 10.1038/s41467-021-21240-1

Wakahara, S., Konoshita, T., Mizuno, S., Motomura, M., Aoyama, C., Makino, Y., et al. (2007). Synergistic expression of angiotensin-converting enzyme (ACE) and ACE2 in human renal tissue and confounding effects of hypertension on the ACE to ACE2 ratio. *Endocrinology* 148, 2453–2457. doi: 10.1210/en.2006-1287

Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T., and Veesler, D. (2020). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. *Cells* 181, 281–292. doi: 10.1016/j.cell.2020.02.058

Wang, K., Chen, W., Zhang, Z., Deng, Y., Lian, J. Q., Peng, D., et al. (2020). CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. *Signal Transduct. Target. Ther.* 5:283. doi: 10.1038/s41392-020-00426-x

Wang, H., Ji, Y., Wu, G., Sun, K., Sun, Y., Li, W., et al. (2015). L-tryptophan activates mammalian target of rapamycin and enhances expression of tight junction proteins in intestinal porcine epithelial cells. *J. Nutr.* 145, 1156–1162. doi: 10.3945/jn.114.209817

Wang, C., Jin, R., Zhu, X., Yan, J., and Li, G. (2015). Function of CD147 in atherosclerosis and atherothrombosis. *J. Cardiovasc. Transl. Res.* 8, 59–66. doi: 10.1007/s12265-015-9608-6

Wang, F., Lu, X., Peng, K., Zhou, L., Li, C., Wang, W., et al. (2014). COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla. *Am. J. Physiol. Ren. Physiol.* 307, F25–F32. doi: 10.1152/ajprenal.00548.2013

Wang, W., Luo, L., Lu, H., Chen, S., Kang, L., and Cui, F. (2015). Angiotensin-converting enzymes modulate aphid-plant interactions. *Sci. Rep.* 5:8885. doi: 10.1038/srep08885

Wang, C., Wang, S., Li, D., Wei, D. Q., Zhao, J., and Wang, J. (2020). Human intestinal defensin 5 inhibits SARS-CoV-2 invasion by cloaking ACE2. *Gastroenterology* 159, 1145–1147.e4. doi: 10.1053/j.gastro.2020.05.015

Wang, Q., Zhang, Y., Wu, L., Niu, S., Song, C., Zhang, Z., et al. (2020). Structural and functional basis of SARS-CoV-2 entry by using human ACE2. *Cells* 181, 894–904.e9. doi: 10.1016/j.cell.2020.03.045

Wang, M. Y., Zhao, R., Gao, L. J., Gao, X. F., Wang, D. P., and Cao, J. M. (2020). SARS-CoV-2: structure, biology, and structure-based therapeutics development. *Front. Cell. Infect. Microbiol.* 10:587269. doi: 10.3389/fcimb.2020.587269

Watanabe, T., Barker, T. A., and Berk, B. C. (2005). Angiotensin II and the endothelium: diverse signals and effects. *Hypertension* 45, 163–169. doi: 10.1161/01.HYP.0000153321.13792.b9

Wei, C., Shan, K. J., Wang, W., Zhang, S., Huan, Q., and Qian, W. (2021). Evidence for a mouse origin of the SARS-CoV-2 omicron variant. *J. Genet. Genom.* 48, 1111–1121. doi: 10.1016/j.jgg.2021.12.003

Wenzel, J., Lampe, J., Müller-Fielitz, H., Schuster, R., Zille, M., Müller, K., et al. (2021). The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. *Nat. Neurosci.* 24, 1522–1533. doi: 10.1038/s41593-021-00926-1

Wicik, Z., Eyileten, C., Jakubik, D., Simoes, S. N., Martins, D. C. Jr., Pavao, R., et al. (2020). ACE2 interaction networks in COVID-19: a physiological framework for prediction of outcome in patients with cardiovascular risk factors. *J. Clin. Med.* 9:3743. doi: 10.3390/jcm9113743

Wright, J. M. (2000). Choosing a first-line drug in the management of elevated blood pressure: what is the evidence? 3: angiotensin-converting-enzyme inhibitors. *AJC* 163, 293–296.

Wu, Y.-H., Li, J.-Y., Wang, C., Zhang, L.-M., and Qiao, H. (2017). The ACE2 G8790A polymorphism: involvement in type 2 diabetes mellitus combined with cerebral stroke. *J. Clin. Lab. Anal.* 31:e22033. doi: 10.1002/jla.22033

Wysocki, J., Garcia-Halpin, L., Ye, M., Maier, C., Sowers, K., Burns, K. D., et al. (2013). Regulation of urinary ACE2 in diabetic mice. *Am. J. Physiol. Physiol.* 305, F600–F611. doi: 10.1152/ajprenal.00600.2012

Xiao, M., Zhang, Y., Zhang, S., Qin, X., Xia, P., Cao, W., et al. (2020). Antiphospholipid antibodies in critically ill patients with coronavirus disease 2019 (COVID-19). *Arthritis Rheum.* 72, 1998–2004. doi: 10.1002/art.41425

Xiao, F., Zimpelmann, J., Agaybi, S., Gurley, S. B., Puente, L., and Burns, K. D. (2014). Characterization of angiotensin-converting enzyme 2 ectodomain shedding from mouse proximal tubular cells. *PLoS One* 9:e85958. doi: 10.1371/journal.pone.0085958

Xie, X., Chen, J., Wang, X., Zhang, F., and Liu, Y. (2006). Age-and genderrelated difference of ACE2 expression in rat lung. *Life Sci.* 78, 2166–2171. doi: 10.1016/j.lfs.2005.09.038

Xie, Y., Xu, E., Bowe, B., and Al-Aly, Z. (2022). Long-term cardiovascular outcomes of COVID-19. *Nat. Med.* 28, 583–590. doi: 10.1038/s41591-022-01689-3

Xu, Q., Jensen, D. D., Peng, H., and Feng, Y. (2016). The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure. *Pharmacol. Ther.* 164, 126–134. doi: 10.1016/j.pharmthera.2016.04.006

Xu, Y., and Li, Y. (2021). MicroRNA-28-3p inhibits angiotensin-converting enzyme 2 ectodomain shedding in 293T cells treated with the spike protein of severe acute respiratory syndrome coronavirus 2 by targeting a disintegrin and metalloproteinase 17. *Int. J. Mol. Med.* 48:189. doi: 10.3892/ijmm.2021.5022

Xu, C., Wang, A., Marin, M., Honnen, W., Ramasamy, S., Porter, E., et al. (2021). Human Defensins inhibit SARS-CoV-2 infection by blocking viral entry. *Viruses* 13:1246. doi: 10.3390/v13071246

Xu, H., Zhong, L., Deng, J., Peng, J., Dan, H., Zeng, X., et al. (2020). High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. *Int. J. Oral Sci.* 12-8. doi: 10.1038/s41368-020-0074-x

Xue, B., Zhang, Z., Roncari, C. F., Guo, F., and Johnson, A. K. (2012). Aldosterone acting through the central nervous system sensitizes angiotensin II-induced hypertension. *Hypertension* 60, 1023–1030. doi: 10.1161/HYPERTENSIONAHA.112.196576

Yamamoto, N., Nishida, N., Yamamoto, R., Gojobori, T., Shimotohno, K., Mizokami, M., et al. (2021). Angiotensin-converting enzyme (ACE) 1 gene polymorphism and phenotypic expression of COVID-19 symptoms. *Gene* 12:1572. doi: 10.3390/genes12101572

Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., Zhou, Q., et al. (2020). Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. *Science* 367, 1444–1448. doi: 10.1126/science.abb2762

Yang, J. M., Dong, M., Meng, X., Zhao, Y. X., Yang, X. Y., Liu, X. L., et al. (2013). Angiotensin-(1-7) dose-dependently inhibits atherosclerotic lesion formation and enhances plaque stability by targeting vascular cells. *Arteriosc. Thromb. Vascular Biol.* 33, 1978–1985. doi: 10.1161/ATVBAHA.113.301320

Yang, P., Gu, H., Zhao, Z., Wang, W., Cao, B., Lai, C., et al. (2014). Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. *Sci. Rep.* 4:7027. doi: 10.1038/srep07027
Yang, M., Zhao, J., Xing, L., and Shi, L. (2015). The association between angiotensin-converting enzyme 2 polymorphisms and essential hypertension risk: a meta-analysis involving 14, 122 patients. *J. Renin-Angiotensin-Aldosterone Syst.* 16, 1240–1244. doi: 10.1177/1470320314549221

Yen, H. L., Sit, T. H. C., Brackman, C. J., Chuk, S. S. Y., Gu, H., Tam, K. W. S., et al. (2022). Transmission of SARS-CoV-2 delta variant (AY.127) from pet hamsters to humans leading to onward human-to-human transmission: a case study. *Lancet* 399, 1070–1078. doi: 10.1016/S0140-6736(22)00326-9

Yi, L., Gu, Y. H., Wang, X. L., An, L. Z., Xie, X. D., Shao, W., et al. (2006). Association of ACE, ACE2 and UTS2 polymorphisms with essential hypertension in Han and Dongxiang populations from North-Western China. *J. Int. Med. Res.* 34, 272–283. doi: 10.1177/147323000603400306

Yim, H. E., and Yoo, K. H. (2008). Renin-angiotensin system-considerations for hypertension and kidney. *Electrol. Blood Press.* 6, 42–50. doi: 10.5049/EBP.2008.6.1.42

Yu, H. Q., Sun, B. Q., Fanf, Z. F., Zhao, J. C., Liu, X. Y., Li, Y. M., et al. (2020). Distinct features of SARS-CoV-2-specific IgA response in COVID-19 patients. *Eur. Respir. J.* 56:2001526. doi: 10.1183/13993003.01526-2020

Yu, C., Tang, W., Wang, Y., Shen, Q., Wang, B., Cai, C., et al. (2016). Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry. *Cancer Lett.* 376, 268–277. doi: 10.1016/j. canlet.2016.04.006

Zhang, H., and Baker, A. (2017). Recombinant human ACE2: acting out angiotensin II in ARDS therapy. *Crit. Care* 21:305. doi: 10.1186/s13054-017-1882-z

Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., et al. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. *Science* 370:eabd4570. doi: 10.1126/science.abd4570

Zhang, J., Dong, J., Martin, M., He, M., Gongol, B., Marin, T. L., et al. (2018). AMP-activated protein kinase phosphorylation of ACE2 in endothelium mitigates pulmonary hypertension. *Am. J. Respir. Crit. Care Med.* 198, 509–520. doi: 10.1164/rccm.201712-2570OC

Zhang, Q., Gefter, J., Sneddon, W. B., Mamonava, T., and Friedman, P. A. (2021). ACE2 interaction with cytoplasmic PDZ protein enhances SARS-CoV-2 invasion. *iScience* 24:102770. doi: 10.1016/j.isci.2021.102770

Zhang, S., Liu, Y., Wang, X., Yang, L., Li, H., Wang, Y., et al. (2020). SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. *J. Hematol. Oncol.* 13:120. doi: 10.1186/s13045-020-00954-7

Zhang, X. J., Qin, J. J., Cheng, X., Shen, L., Zhao, Y. C., Yuan, Y., et al. (2020). In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. *Cell Metab.* 32, 176–187. doi: 10.1016/j. cmet.2020.06.015.e4

Zhang, C., Shen, L., Le, K. J., Pan, M. M., Kong, L. C., Gu, Z. C., et al. (2020). Incidence of venous thromboembolism in hospitalized coronavirus disease 2019 patients: a systematic review and meta-analysis. *Front. Cardiovasc. Med.* 7:151. doi: 10.3389/fcvm.2020.00151

Zhang, H., Wada, J., Hida, K., Tsuchiyama, Y., Hiragushi, K., Shikata, K., et al. (2001). Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. *J. Biol. Chem.* 276, 17132–17139. doi: 10.1074/jbc.M006723200

Zhang, Z. Z., Wang, W., Jin, H. Y., Chen, X., Cheng, Y. W., Xu, Y. L., et al. (2017). Apelin is a negative regulator of angiotensin II-mediated adverse myocardial

remodeling and dysfunction. *Hypertension* 70, 1165-1175. doi: 10.1161/HYPERTENSIONAHA.117.10156

Zhang, Y., Xiao, M., Zhang, S., Xia, P., Cao, W., Jiang, W., et al. (2020). Coagulopathy and antiphospholipid antibodies in patients with Covid-19. *N. Engl. J. Med.* 382:e38. doi: 10.1056/NEJMc2007575

Zhang, L., Zhang, Y., Qin, X., Jiang, X., Zhang, J., Mao, L., et al. (2022). Recombinant ACE2 protein protects against acute lung injury induced by SARS-CoV-2 spike RBD protein. *Crit. Care* 26:171. doi: 10.1186/s13054-022-04034-9

Zhang, P., Zhu, L., Cai, J., Lei, F., Qin, J. J., Xie, J., et al. (2020). Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. *Circ. Res.* 126, 1671–1681. doi: 10.1161/CIRCRESAHA. 120.317242

Zhao, J., Yuan, Q., Wang, H., Liu, W., Liao, X., Su, Y., et al. (2020). Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. *Clin. Infect. Dis.* 71, 2027–2034. doi: 10.1093/cid/ciaa344

Zhao, Y., Zhao, Z., Wang, Y., Zhou, Y., Ma, Y., and Zuo, W. (2020). Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. *Am. J. Respir. Crit. Care Med.* 202, 756–759. doi: 10.1164/rccm.202001-0179LE

Zheng, M., Gao, Y., Wang, G., Song, G., Liu, S., Sun, D., et al. (2020). Functional exhaustion of antiviral lymphocytes in COVID-19 patients. *Cell. Mol. Immunol.* 17, 533–535. doi: 10.1038/s41423-020-0402-2

Zhou, P., Yang, X. L., Wang, X. G., Hu, B., Zhang, L., Zhang, W., et al. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. *Nature* 579, 270–273. doi: 10.1038/s41586-020-02012-7

Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., et al. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. *Lancet* 395, 1054–1062. doi: 10.1016/S0140-6736(20) 30566-3

Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. *N. Engl. J. Med.* 382, 727–733. doi: 10.1056/NEJMoa2001017

Zhuang, M. W., Cheng, Y., Zhang, J., Jiang, X. M., Wang, L., Deng, J., et al. (2020). Increasing host cellular receptor-angiotensin-converting enzyme 2 (ACE2) expression by coronavirus may facilitate 2019-nCoV (or SARS-CoV2) infection. *J. Med. Virol.* 92, 2693–2701. doi: 10.1002/jmv.26139

Ziegler, C. G. K., Allon, S. J., Nyquist, S. K., Mbano, I. M., Miao, V. N., Tzouanas, C. N., et al. (2020). SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. *Cells* 181, 1016–1035.e19. doi: 10.1016/j.cell. 2020. 04.035

Zou, X., Chen, K., Zou, J., Han, P., Hao, J., and Han, Z. (2020). Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. *Front. Med.* 14, 185–192. doi: 10.1007/s11684-020-0754-0

Zoufaly, A., Poglitsch, M., Aberle, J. H., Hoepler, W., Seitz, T., Traugott, M., et al. (2020). Human recombinant soluble ACE2 in severe COVID-19. *Lancet Respir. Med.* 8, 115–120. doi: 10.1016/S2213-2600(20)30418-5

Zuo, Y., Yalavarthi, S., Shi, H., Gockman, K., Zuo, M., Madison, J. A., et al. (2020). Neutrophil extracellular traps in COVID-19. *JCI Insight* 5:e138999. doi: 10.1172/jci. insight.138999
Yang, M., Zhao, J., Xing, L., and Shi, L. (2015). The association between angiotensin-converting enzyme 2 polymorphisms and essential hypertension risk: a meta-analysis involving 14, 122 patients. *J. Renin-Angiotensin-Aldosterone Syst.* 16, 1240-1244. doi: 10.1177/1470320314549221

Yen, H. L., Sit, T. H. C., Brackman, C. J., Chuk, S. S. Y., Gu, H., Tam, K. W. S., et al. (2022). Transmission of SARS-CoV-2 delta variant (AY.127) from pet hamsters to humans leading to onward human-to-human transmission: a case study. *Lancet* 399, 1070-1078. doi: 10.1016/S0140-6736(22)00326-9

Yi, L., Gu, Y. H., Wang, X. L., An, L. Z., Xie, X. D., Shao, W., et al. (2006). Association of ACE, ACE2 and UTS2 polymorphisms with essential hypertension in Han and Dongxiang populations from North-Western China. *J. Int. Med. Res.* 34, 272-283. doi: 10.1177/147323000603400306

Yim, H. E., and Yoo, K. H. (2008). Renin-angiotensin system-considerations for hypertension and kidney. *Electrol. Blood Press.* 6, 42-50. doi: 10.5049/EBP.2008.6.1.42

Yu, H. Q., Sun, B. Q., Fanf, Z. F., Zhao, J. C., Liu, X. Y., Li, Y. M., et al. (2020). Distinct features of SARS-CoV-2-specific IgA response in COVID-19 patients. *Eur. Respir. J.* 56:2001526. doi: 10.1183/13993003.01526-2020

Yu, C., Tang, W., Wang, Y., Shen, Q., Wang, B., Cai, C., et al. (2016). Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry. *Cancer Lett.* 376, 268-277. doi: 10.1016/j. canlet.2016.04.006

Zhang, H., and Baker, A. (2017). Recombinant human ACE2: acting out angiotensin II in ARDS therapy. *Crit. Care* 21:305. doi: 10.1186/s13054-017-1882-z

Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., et al. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. *Science* 370:eabd4570. doi: 10.1126/science.abd4570

Zhang, J., Dong, J., Martin, M., He, M., Gongol, B., Marin, T. L., et al. (2018). AMP-activated protein kinase phosphorylation of ACE2 in endothelium mitigates pulmonary hypertension. *Am. J. Respir. Crit. Care Med.* 198, 509-520. doi: 10.1164/rccm.201712-2570OC

Zhang, Q., Gefter, J., Sneddon, W. B., Mamonava, T., and Friedman, P. A. (2021). ACE2 interaction with cytoplasmic PDZ protein enhances SARS-CoV-2 invasion. *iScience* 24:102770. doi: 10.1016/j.isci.2021.102770

Zhang, S., Liu, Y., Wang, X., Yang, L., Li, H., Wang, Y., et al. (2020). SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. *J. Hematol. Oncol.* 13:120. doi: 10.1186/s13045-020-00954-7

Zhang, X. J., Qin, J. J., Cheng, X., Shen, L., Zhao, Y. C., Yuan, Y., et al. (2020). In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. *Cell Metab.* 32, 176-187. doi: 10.1016/j. cmet.2020.06.015.e4

Zhang, C., Shen, L., Le, K. J., Pan, M. M., Kong, L. C., Gu, Z. C., et al. (2020). Incidence of venous thromboembolism in hospitalized coronavirus disease 2019 patients: a systematic review and meta-analysis. *Front. Cardiovasc. Med.* 7:151. doi: 10.3389/fcvm.2020.00151

Zhang, H., Wada, J., Hida, K., Tsuchiyama, Y., Hiragushi, K., Shikata, K., et al. (2001). Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. *J. Biol. Chem.* 276, 17132-17139. doi: 10.1074/jbc.M006723200

Zhang, Z. Z., Wang, W., Jin, H. Y., Chen, X., Cheng, Y. W., Xu, Y. L., et al. (2017). Apelin is a negative regulator of angiotensin II-mediated adverse myocardial

remodeling and dysfunction. *Hypertension* 70, 1165-1175. doi: 10.1161/HYPERTENSIONAHA.117.10156

Zhang, Y., Xiao, M., Zhang, S., Xia, P., Cao, W., Jiang, W., et al. (2020). Coagulopathy and antiphospholipid antibodies in patients with Covid-19. *N. Engl. J. Med.* 382:e38. doi: 10.1056/NEJMc2007575

Zhang, L., Zhang, Y., Qin, X., Jiang, X., Zhang, J., Mao, L., et al. (2022). Recombinant ACE2 protein protects against acute lung injury induced by SARS-CoV-2 spike RBD protein. *Crit. Care* 26:171. doi: 10.1186/s13054-022-04034-9

Zhang, P., Zhu, L., Cai, J., Lei, F., Qin, J. J., Xie, J., et al. (2020). Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. *Circ. Res.* 126, 1671-1681. doi: 10.1161/CIRCRESAHA. 120.317242

Zhao, J., Yuan, Q., Wang, H., Liu, W., Liao, X., Su, Y., et al. (2020). Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. *Clin. Infect. Dis.* 71, 2027-2034. doi: 10.1093/cid/ciaa344

Zhao, Y., Zhao, Z., Wang, Y., Zhou, Y., Ma, Y., and Zuo, W. (2020). Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. *Am. J. Respir. Crit. Care Med.* 202, 756-759. doi: 10.1164/rccm.202001-0179LE

Zheng, M., Gao, Y., Wang, G., Song, G., Liu, S., Sun, D., et al. (2020). Functional exhaustion of antiviral lymphocytes in COVID-19 patients. *Cell. Mol. Immunol.* 17, 533-535. doi: 10.1038/s41423-020-0402-2

Zhou, P., Yang, X. L., Wang, X. G., Hu, B., Zhang, L., Zhang, W., et al. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. *Nature* 579, 270-273. doi: 10.1038/s41586-020-02012-7

Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., et al. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. *Lancet* 395, 1054-1062. doi: 10.1016/S0140-6736(20) 30566-3

Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. *N. Engl. J. Med.* 382, 727-733. doi: 10.1056/NEJMoa2001017

Zhuang, M. W., Cheng, Y., Zhang, J., Jiang, X. M., Wang, L., Deng, J., et al. (2020). Increasing host cellular receptor-angiotensin-converting enzyme 2 (ACE2) expression by coronavirus may facilitate 2019-nCoV (or SARS-CoV2) infection. *J. Med. Virol.* 92, 2693-2701. doi: 10.1002/jmv.26139

Ziegler, C. G. K., Allon, S. J., Nyquist, S. K., Mbano, I. M., Miao, V. N., Tzouanas, C. N., et al. (2020). SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. *Cells* 181, 1016-1035.e19. doi: 10.1016/j.cell. 2020. 04.035

Zou, X., Chen, K., Zou, J., Han, P., Hao, J., and Han, Z. (2020). Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. *Front. Med.* 14, 185-192. doi: 10.1007/s11684-020-0754-0

Zoufaly, A., Poglitsch, M., Aberle, J. H., Hoepler, W., Seitz, T., Traugott, M., et al. (2020). Human recombinant soluble ACE2 in severe COVID-19. *Lancet Respir. Med.* 8, 115-120. doi: 10.1016/S2213-2600(20)30418-5

Zuo, Y., Yalavarthi, S., Shi, H., Gockman, K., Zuo, M., Madison, J. A., et al. (2020). Neutrophil extracellular traps in COVID-19. *JCI Insight* 5:e138999. doi: 10.1172/jci. insight.138999