Angiotensin-(1-7): new perspectives in atherosclerosis treatment

Abstract

Angiotensin (Ang)-(1-7) is recognized as a new bioactive peptide in renin-angiotensin system (RAS). Ang-(1-7) is a counter-regulatory mediator of Ang-II which appears to be protective against cardiovascular disease. Recent studies have found that Ang-(1-7) played an important role in reducing smooth muscle cell proliferation and migration, improving endothelial function and regulating lipid metabolism, leading to inhibition of atherosclerotic lesions and increase of plaque stability. Although clinical application of Ang-(1-7) is restricted due to its pharmacokinetic properties, identification of stabilized compounds, including more stable analogues and specific delivery compounds, has enabled clinical application of Ang-(1-7). In this review, we discussed recent findings concerning the biological role of Ang-(1-7) and related mechanism during atherosclerosis development. In addition, we highlighted the perspective to develop therapeutic strategies using Ang-(1-7) to treat atherosclerosis.

Keywords: Angiotensin-(1-7); Atherosclerosis; Endothelial function; Smooth muscle cell function.

Figure 1.. The role of Ang-(1–7) in atherosclerosis.

Ang-(1–7) effectively suppresses expression of endothelial cell adhesion molecules, such as VCAM-1 and ICAM-1, resulting in reduction of monocyte adhesion into endothelial layer and subsequent decreased macrophage recruitment in atherosclerotic plaque. Ang-(1–7) increases eNOS expression, resulting in endothelium-dependent vasodilation. In addition, Ang-(1–7) stimulates proliferation of endothelial progenitor cell, regenerating the injured endothelial layer. Ang-(1–7) also causes a great reduction of thrombus formation. Vascular smooth muscle cell migration and proliferation can be also inhibited by Ang-(1–7). Ang-(1–7) effectively modulates lipid metabolism through reducing total cholesterol and triglycerides levels. Finally, Ang-(1–7) suppresses the formation of atherosclerotic lesion, and improves plaque stability by reducing proinflammatory cytokines levels, matrix metalloproteinases activities, macrophage contents and necrotic core in the plaque. Ang-(1-7): Angiotensin-(1-7); eNOS: endothelial nitric oxide synthase; ICAM-1: intercellular cell adhesion molecule 1; IL-6: Interleukin 6; MCP-1: monocyte chemotactic protein; SMC: smooth muscle cells; TNF-α: tumor necrosis factor α; VCAM-1: vascular cell adhesion molecule 1; VSMC: vascular smooth muscle cell.

Figure 2.. The comparison of ACE/Ang-II/AT1 axis and ACE2/Ang-(1–7)/MAS axis.

Ang-I is cleaved by ACE into Ang-II. In contrast, Ang-I is cleaved by ACE2 and further cleaved by ACE, generating Ang-(1–7). Ang-(1–7) can counteract the effects of Ang-II, mediating vasodilation, blood pressure reduction, anti-proliferation and sodium secretion. ACE: angiotensin converting enzyme; Ang-II: angiotensin II; Ang-I: angiotensin I; Ang-(1-7): angiotensin-(1-7); AT1: angiotensin II receptor type 1; PEP: prolylendopeptidase; PCP: prolylcarboxypeptidase; MAS: G-coupled protein receptor of Ang-(1-7); MMP8: matrix metalloproteinase 8.