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

Abstract

Introduction: Angiotensin-converting enzyme 2 (ACE2) is a new member of the renin-angiotensin system (RAS) and it has been proposed that ACE2 is a potential therapeutic target for the control of cardiovascular disease. The effect of losartan on the ACE2 activity in atherosclerosis was studied. Methods: Atherosclerosis was induced in New Zealand white rabbits by high-cholesterol diet for 3 months. An Angiotensin II (Ang II) receptor blocker (losartan, 25 mg/kg/d) was given for 3 months. ACE2 activity was measured by fluorescence assay and the extent of atherosclerosis was evaluated by H&E and Oil Red O staining. In addition, the effect of losartan on ACE2 activity in smooth muscle cells (SMCs) in vitro was also evaluated. Results: Losartan increased ACE2 activity in atherosclerosis in vivo and SMCs in vitro. Losartan inhibited atherosclerotic evolution. Addition of losartan blocked Ang II-induced down-regulation of ACE2 activity, and blockade of extracellular signal-regulated kinase (ERK1/2) with PD98059 prevented Ang II-induced down-regulation of ACE2 activity. Conclusions: The results showed that ACE2 activity was regulated in atherosclerotic plaque by losartan, which may play an important role in treatment of atherosclerosis. The mechanism involves Ang II-AT1R-mediated mitogen-activated protein kinases, MAPKs (MAPKs) signaling pathway.

Relationship between circulating levels of angiotensin-converting enzyme 2-angiotensin-(1–7)-MAS axis and coronary heart disease

“…Several lines of evidence have showed the role of ACE2-Ang-(1-7)-Mas axis in atherosclerosis. ACE2 protein is expressed in endothelial cells, smooth muscle cells and macrophages in aortic and coronary atherosclerotic lesions [12,13]. ACE2 overexpression significantly inhibits early atherosclerotic lesions development both in human endothelial cells in vitro and in apoE-deficient mice in vivo [14].…”

Low-sodium diet induces atherogenesis regardless of lowering blood pressure in hypertensive hyperlipidemic mice

“…Considering that ANG II causes insulin resistance and glucose intolerance [4], in the present study, the low plasma TG and NEFA concentrations in the Los-treated mice may have resulted from AT1 receptor antagonism, a condition that can ameliorate insulin sensitivity. Moreover, negative effects of ANG II on the arterial wall, such as the down-regulation of angiotensin-converting enzyme 2 (ACE2) expression [34], may have been prevented in the Los-treated mice (H-LS+Los). In the current study, reductions in plasma TG and NEFA levels, together with other anti-atherosclerotic mechanisms triggered by the AT1 receptor antagonism, may explain the lower lipid infiltration observed in the vascular wall of the Los-treated mice compared with the N-LS mice.…”

Involvement of the Renin‐Angiotensin System in Atherosclerosis

“…ACE2 and exogenous Ang-(1-7) significantly inhibit early atherosclerotic lesion formation by preserving endothelial function and inhibiting of an inflammatory response in ApoE-/-mice [118,119]. ACE2 activity and protein production were increased in atherosclerotic plaques treated with losartan in vivo in and in vitro in VSMCs [120]. Candesartan treatment restores vasoprotective and atheroprotective effects of the ACE2/ Ang (1-7)/Mas receptor axis in high-cholesterol diet-fed ApoE-/-mice due to the inhibition of the pro-inflammatory-redox AT1R-mediated mechanism [121].…”