Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated AngII-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERKp38, JAK-STAT, and AngII-ROS-NF-κB signaling pathways and upregulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis.atherosclerosis | endothelial cell | gene therapy | smooth muscle cell | signaling pathway A ccumulating evidence indicates that endothelial cell (EC) dysfunction and the proliferation and migration of vascular smooth muscle cells (VSMCs) are salient features of early atherosclerotic lesions, and that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of atherosclerosis (1, 2). Angiotensin II (AngII) promotes EC dysfunction and VSMC proliferation and migration by increasing the expression of monocyte chemoattractant protein 1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), leading to aggravation of atherosclerotic lesions (3-5). Delivery of ACE inhibitors or AngII type 1 receptor (AT 1 R) blockers to limit AngII bioactivity is an effective approach against atherosclerosis.Recent studies show that endogenous levels of AngII are regulated by the opposing action of two carboxypeptidases, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). The latter is thought to counterbalance ACE by cleaving AngI into the inactive angiotensin 1-9 and cleaving AngII into the vasodilating and antiproliferative angiotensin 1-7 [Ang(1-7)]. ACE2 is thus considered a potential therapeutic target of RAS for the treatment of cardiovascular diseases by virtue of its key role in the formation of vasoprotective peptides from AngII (6-8). Our recent study using a rabbit atherosclerosis model showed that ACE2 overexpression stabilized aortic plaques at a late stage and attenuated the progression of early atherosclerotic lesions. These ther...

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

“…3,[84][85][86][87][88][89] CONCLUSIONS In summary, Ang-(1-7) is generated in the vascular wall and other tissues from Ang II by ACE2, resulting in a decrease in Ang II levels and an increase in Ang-(1-7) concentrations in the vessels. Thus, the ACE2-Ang-(1-7)-Mas axis counterregulates the classic RAAS in tissues responsible for blood pressure regulation and cardiovascular homeostasis.…”

“…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.…”

Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis

“…The immunohistochemical staining was performed as previously described 27. Sections were incubated with the primary antibodies against α‐SMA (1:200; Abcam, ab5694), monocyte/macrophage antigen [MOMA‐2] (1:200; MCA519G; AbD, UK), MMP2 (1:250; NovusBio, NB200‐193) and MMP9 (1:100; Abcam, ab38898).…”

ACE2 activity was increased in atherosclerotic plaque by losartan: Possible relation to anti-atherosclerosis

“…Our study showed that ACE2 overexpression attenuated the progression of lesions and stabilized atherosclerotic plaques in rabbits, which were formed by endothelial injury and an atherogenic diet. 14 Sahara et al reported that ACE2 gene knock-out in mouse increased the severity of atherosclerosis and produced an inflammatory response in plaque, suggesting that ACE2 is an important role in anti-atherosclerosis. 15 Thatcher et al found that ACE2 deficiency increased atherosclerotic area and inflammatory response through regulation of the ratio of Ang II/Ang-(1-7) peptides.…”