Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets

Fan Jiang, Jianmin Yang, Yongtao Zhang, Mei Dong, Shuangxi Wang, Qunye Zhang, Fang Fang Liu, Kai Zhang, Cheng Zhang, Fan Jiang, Jianmin Yang, Yongtao Zhang, Mei Dong, Shuangxi Wang, Qunye Zhang, Fang Fang Liu, Kai Zhang, Cheng Zhang

Abstract

The renin-angiotensin system (RAS) has pivotal roles in the regulation of normal physiology and the pathogenesis of cardiovascular disease. Angiotensin-converting enzyme (ACE) 2, and its product angiotensin 1-7, are thought to have counteracting effects against the adverse actions of other, better known and understood, members of the RAS. The physiological and pathological importance of ACE2 and angiotensin 1-7 in the cardiovascular system are not completely understood, but numerous experimental studies have indicated that these components have protective effects in the heart and blood vessels. Here, we provide an overview on the basic properties of ACE2 and angiotensin 1-7 and a summary of the evidence from experimental and clinical studies of various pathological conditions, such as hypertension, atherosclerosis, myocardial remodelling, heart failure, ischaemic stroke, and diabetes mellitus. ACE2-mediated catabolism of angiotensin II is likely to have a major role in cardiovascular protection, whereas the relevant functions and signalling mechanisms of actions induced by angiotensin 1-7 have not been conclusively determined. The ACE2-angiotensin 1-7 pathway, however, might provide a useful therapeutic target for the treatment of cardiovascular disease, especially in patients with overactive RAS.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1. Overview of the ACE2–Ang 1–7…
Figure 1. Overview of the ACE2–Ang 1–7 pathway.
ACE2 converts Ang II to Ang 1–7. ACE2 can also convert Ang I to Ang 1–9, which is then cleaved by either NEP or ACE to yield Ang 1-7. The membrane-bound ACE2 can be cleaved by the metalloproteinase ADAM17, forming a soluble form of ACE2. The physiological relevance of soluble ACE2 is not fully understood. Abbreviations: ACE, angiotensin-converting enzyme; Ang, angiotensin; NEP, neutral endopeptidase; PCP, prolyl carboxypeptidase. PowerPoint slide
Figure 2. Structure of the extracellular domain…
Figure 2. Structure of the extracellular domain (from Ser19 to Asp615) of human ACE2.
In this image, the extracellular domain is arbitrarily divided into two subdomains (shown in green and purple), forming a deep cleft that is proposed to be the active site for substrate binding and catalysis. The catalytic domain (amino acids 147–555) has a substrate binding region (amino acids 273–345) and a typical HEMGH metalloproteinase zinc-binding site (amino acids 374–378). The regions shown in ball-and-stick figuration are proposed binding sites for the ACE2 inhibitor MLN-4760. Abbreviation: ACE2, angiotensin-converting enzyme 2. Amino acid sequence annotations are derived from Towler, P. et al. J. Biol. Chem.279, 17996–18007 (2004). PowerPoint slide
Figure 3. Potential effects of ACE2 and…
Figure 3. Potential effects of ACE2 and Ang 1–7 on blood-pressure regulation.
ACE2 is known to cause reductions in blood pressure, whereas various experimental evidence has indicated no effects, hypotensive effects, and hypertensive effects of Ang 1–7. Abbreviations: ACE2, angiotensin-converting enzyme 2; Ang, angiotensin; CNS, central nervous system; PVN, paraventricular nucleus, RVLM, rostral ventrolateral medulla. PowerPoint slide
Figure 4. Protective effects of ACE2 and…
Figure 4. Protective effects of ACE2 and Ang 1–7 on atherosclerosis and resultant myocardial infarction and stroke.
Abbreviations: ACE2, angiotensin-converting enzyme 2; Ang, angiotensin; VSMC, vascular smooth muscle cell. PowerPoint slide
Figure 5. Potential protective effects of ACE2…
Figure 5. Potential protective effects of ACE2 and Ang 1–7 on pathological cardiac remodelling and heart failure.
Abbreviations: ACE2, angiotensin-converting enzyme 2; Ang, angiotensin. PowerPoint slide
Figure 6. Beneficial effects of ACE2 and…
Figure 6. Beneficial effects of ACE2 and Ang 1-7 on insulin resistance and diabetes.
The conversion of Ang II to Ang 1-7 by ACE2 is increased in type 1 and in type 2 diabetes. Ang 1-7 increases insulin sensitivity and glucose uptake through activation of PI3K–Akt signalling and reduction of pancreatic β-cell apoptosis. Blockade of the effects of ACE2 by MLN-4760, or Ang 1-7 by A-779, might reverse the metabolic effects of ACE2 and Ang 1-7 and thereby worsen vascular complications. Abbreviations: ACE, angiotensin-converting enzyme; Ang, angiotensin; PI3K, phosphatidylinositol 3-kinase. PowerPoint slide

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Source: PubMed

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