Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis

Abstract

dothelium plays a central role in the maintenance of vascular homeostasis. One of the main effectors of endothelial dysfunction is ANG II, and pharmacological approaches to limit ANG II bioactivity remain the cornerstone of cardiovascular therapeutics. Angiotensin converting enzyme-2 (ACE2) has been identified as a critical negative modulator of ANG II bioactivity, counterbalancing the effects of ACE in determining net tissue ANG II levels; however, the role of ACE2 in the vasculature remains unknown. In the present study, we hypothesized that ACE2 is a novel target to limit endothelial dysfunction and atherosclerosis. To this aim, we performed in vitro gain and loss of function experiments in endothelial cells and evaluated in vivo angiogenesis and atherosclerosis in apolipoprotein E-knockout mice treated with AdACE2. ACE2-deficient mice exhibited impaired endothelium-dependent relaxation. Overexpression of ACE2 in human endothelial cells stimulated endothelial cell migration and tube formation, and limited monocyte and cellular adhesion molecule expression; effects that were reversed in ACE2 gene silenced and endothelial cells isolated from ACE2-deficient animals. ACE2 attenuated ANG II-induced reactive oxygen species production in part through decreasing the expression of p22phox. The effects of ACE2 on endothelial activation were attenuated by pharmacological blockade of ANG-(1-7) with A779. ACE2 promoted capillary formation and neovessel maturation in vivo and reduced atherosclerosis in apolipoprotein E-knockout mice These data indicate that ACE2, in an ANG-(1-7)-dependent fashion, functions to improve endothelial homeostasis via a mechanism that may involve attenuation of NADPHox-induced reactive oxygen species production. ACE2-based treatment approaches may be a novel approach to limit aberrant vascular responses and atherothrombosis. endothelium; atherogenesis; angiogenesis THE ENDOTHELIUM FUNCTIONS as a protective biocompatible barrier between all tissues and the circulating blood (17). Endothelial cells also function as a selective sieve to facilitate bidirectional passage of macromolecules and blood gases to and from tissues and blood (17). The strategic location of the endothelium allows it to "sense" changes in hemodynamic forces and blood-borne signals and "respond" by releasing a number of autocrine and paracrine substances. A balanced release of these bioactive factors facilitates vascular homeostasis. Endothelial cell dysfunction disrupts this balance, thereby predisposing the vessel wall to vasoconstriction, leukocyte adherence, platelet activation, mitogenesis, prooxidation, thrombosis, impaired coagulation, vascular inflammation, and atherosclerosis. Improving endothelial function is a major goal of cardiovascular risk reduction.The renin-angiotensin system (RAS) is a pivotal transducer of cardiovascular function and plays a causal role in the development and progression of endothelial dysfunction and atherosclerosis (7,15,17). RAS supports a series of complex enzymatic reactions that culmina...

ACE2–angiotensin-(1–7)–Mas axis and oxidative stress in cardiovascular disease

“…80,81 Corroborating these findings, Tesanovic et al 82 recently reported that long-term Ang-(1-7) treatment induces atheroprotective effects in ApoE À/À mice, the most widely used animal model for atherosclerosis. According to the authors, the improvement in endothelial function resulted from an increase in NO bioavailability, as the heptapeptide increased NOS expression and decreased À production.…”

“…Concurrently, it was recently shown that genetic deletion of ACE2 significantly increases 83 plaque formation in atherosclerotic animals, which is decreased by targeted vascular ACE2 overexpression. 80,84 Consequently, these actions of the ACE2-Ang-(1-7)-Mas axis may be exploited in the treatment of atherosclerosis and other vascular diseases.…”

Visfatin activates eNOS via Akt and MAP kinases and improves endothelial cell function and angiogenesis in vitro and in vivo: translational implications for atherosclerosis

“…Oligonucleotide primers for human visfatin were designed from the GeneBank databases (NM_005746) using the ProbeFinder software (Roche Applied Science): (forward) 5Ј-AGGGCTTTGTCATTCCCAGA and (reverse) 5Ј-TGGCCACTGTGATTGGATACC. Primer sequences for eNOS and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) have been reported previously (10,13). For each PCR assay, standard curves were prepared by serial dilutions of cDNA.…”

New Components of the Renin-Angiotensin-Aldosterone System and Oxidative Stress

“…Treatment with azilsartan or Ang-(1-7) attenuated neointimal area, vascular smooth muscle cell proliferation, and superoxide anion, and increased ACE2 mRNA and AT 2 receptor mRNA but not AT 1 receptor mRNA, suggesting blockade of AT 1 receptor coud enhance the activities of the ACE2/ AngⅡ/AT 2 Axis and ACE2/Ang-(1-7)/Mas Axis. The role of ACE2 in the vasculature is also reported, evaluating angiogenesis and atherosclerosis in endothelial cells of apoprotein E-knockout, ACE2-overexpressing and deficient mice [45]. ACE2-deficient mice exhibited impaired endothelium-dependent relaxation.…”