ACE2 (Angiotensin-Converting Enzyme 2)-Mediated Protection From Pulmonary Hypertension: Lung-Gut Axis at Center Stage.

ACE2 (angiotensin-converting enzyme 2) is a multidimensional transmembrane protein that functions as a monocarboxypeptidase, a regulator of intestinal amino acid transport, and as the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) receptor. These functional roles place ACE2 as a central orchestrator controlling the renin-angiotensin system, gut inflammation and microbiota, and in the coronavirus disease 2019 (COVID-19) pandemic, respectively. In particular, these effects culminate and regulate lung disease, including pulmonary hypertension (PH). PH is defined as a resting mean pulmonary arterial pressure >25 mm Hg or a mean pulmonary arterial pressure with exercise >30 mm Hg, which is classified into 5 groups with group 1 representing pulmonary arterial hypertension and group 2 as PH secondary to heart disease. ACE2 generates Ang 1–7 (angiotensin 1–7) by removing the C-terminal amino acid from Ang II; in diseased states, ACE2 is downregulated, and ACE/Ang II/AT 1 R (angiotensin II type 1 receptor) signaling is increased. Ang 1–7 activates its G protein-coupled MasR (Mas receptor) stimulating vasodilation via eNOS stimulation while also activating antifibrotic and antihypertrophic pathways within cardiovascular and pulmonary systems. ACE2 is highly expressed in the goblet, and ciliated cells of the upper airway epithelium in addition to type II alveolar cells of the lungs and the pulmonary vasculature. Increasing ACE2 alleviates pulmonary injury and vascular damage and prevent PH, decreased lung fibrosis, arterial remodeling, and improved right ventricular performance due to a combination of direct action in the lungs and via the ACE2-dependent gut-lung axis. In this issue of Hypertension, Sharma et al used a gain-offunction approach in highlighting the role of ACE2 in alleviating hypoxia-mediated PH presumably through an elevation in ACE2 protein levels as well as through changes in gut microbiota using a global Ace2 knock-in (KI) mice and their wildtype (WT) littermates. WT and Ace2 KI mice were subjected to hypoxic conditions chronically for four weeks upon which WT mice developed PH based on hemodynamic characterization and histological examination illustrated by increased pulmonary arteriole wall thickness, as measured by α-smooth muscle actin staining, and increased right ventricular (RV) fibrosis, as shown by picrosirius red staining. RV hemodynamic assessment of the experimental groups showed that Ace2 KI prevented elevated RV pressures from developing under hypoxia, which was mirrored with the prevention of RV hypertrophy assessed by RV weight and cardiomyocyte morphology. ACE2 tissue (gut, lung, and paraventricular nucleus) and plasma activity were depressed in both WT and Ace2 KI hypoxic mice, though Ace2 KI hypoxic mice still had higher activity levels than WT mice. Importantly, Ace2 KI minimized the marked decrease in serum Ang 1–7 in the hypoxia group while Ang II levels were unaltered providing further evidence that increased ACE2 activity can promote Ang 1–7 formation (Figure). Paraventricular nucleus microglial activation and optical density was decreased in hypoxic Ace2 KI in line with decreased sympathetic stimulation as compared to WT hypoxic mice suggesting that the central nervous system is also involved in mediating these physiological changes. The gut microbiota has emerged as a mediator of various diseases, including metabolic disorders, systemic hypertension, and PH. Alterations in gut microbiota can cause gut epithelial dysfunction and breakdown in the permeability barrier leading to invasion of the host circulation by both microbes and their metabolites. Systemic presence of microbes and microbial metabolites stimulates an immune response driving systemic inflammation and metabolic alterations. Using loss-of-function approaches, ACE2 has been shown to mediate a renin-angiotensin system-independent function regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the gut microbiome. Sharma et al’s study used a gain-of-function approach to demonstrate a crucial role of ACE2 in the gut (and the gut microbiome) in mediating the protective effects against hypoxia-induced PH and RV remodeling. Ace2 KI, which underwent hypoxia, had decreased intestinal fibrosis, muscularis membrane thickening, and an increased amount of goblet cell as compared to WT hypoxic mice, which had a dramatic decrease in microvilli length, a key marker of epithelial barrier dysfunction. There were numerous changes in the gut microbiota composition in fecal samples from WT mice in response to hypoxia, which was distinctly absent in the Ace2 KI group. In particular, the ratio of the Firmicutes and Bacteroides phyla, a conventional marker of gut dysbiosis, decreased in hypoxic WT mice, which was not observed in the hypoxic Ace2 KI group. Fecal microbial transplants from Ace2 KI mice The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Physiology (M.G., G.Y.O.), Division of Cardiology, Department of Medicine (K.W., G.Y.O.), and Mazankowski Alberta Heart Institute (M.G., K.W., G.Y.O.), University of Alberta, Edmonton, Canada. Correspondence to: Gavin Y. Oudit, Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada. Email gavin.oudit@ualberta.ca ACE2 (Angiotensin-Converting Enzyme 2)-Mediated Protection From Pulmonary Hypertension Lung-Gut Axis at Center Stage