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

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.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Both animal and clinical studies have emerged to define a role for ACE2 in regulating the progression of cardiovascular disease and pulmonary arterial hypertension. The activation of pulmonary ACE2 could serve as a novel therapeutic target in vivo (Bradford et al, 2010;Jiang et al, 2014). The ACE2/Ang(1-7) axis seems to be involved in many physiologic and pathophysiological processes in several systems and organs, especially by opposing the detrimental effects of inappropriate overactivation of the ACE/AngII axis (Passos-Silva et al, 2013).…”

Mild Hypokalemia and Supraventricular Ectopy Increases the Risk of Stroke in Community-Dwelling Subjects

“…New studies have elaborated on the hypothesis because the neuronal damage seen in stroke patients could be associated with increased activity of the angiotensin receptor subtype 1 in the brain-specific RAAS system, whereas the expression of the angiotensin receptor subtype 2 in contrast seems to exert neuroprotective effects. [28][29][30] An overactive RAAS systemwith hypokalemia as a possible pseudo marker-could, therefore, as a consequence potentiate subclinical strokes, resulting in more extensive neurological damage, worse symptoms, and subsidiarily more pronounced neurological deficits. The synergistic effect of mild hypokalemia and ESVEA could be a …”

New Approaches in the Treatment of Hypertension

“…48 Interestingly, inhibitors of the classical RAS, including ACE inhibitors and angiotensin receptor blockers (ARBs), increase circulating Ang(1-7) levels, and the Mas antagonist A-779 attenuates the effects of the ACE inhibitors and ARBs, indicating that the 2 RAS axes interact 49 and provide further evidence for the therapeutic potential of the ACE2/Ang(1-7)/ Mas axis in hypertension.…”

“…More recently, components of the RAS that play counterregulatory roles have been identified, characterized and put forward as therapeutic targets for hypertension and other forms of CVD [46][47][48][49][50] ( Figure 2). The carboxypeptidase angiotensin-converting enzyme 2 (ACE2) converts the decapeptide angiotensin I (Ang I) to the Ang(1-9) nonapeptide and the octapeptide Ang II to the Ang(1-7) heptapeptide.…”

“…The relative merits of Mas receptor activation versus ACE2 stimulation are being debated, but all agree that randomized controlled trials in humans with hypertension and related CVDs are needed to assess the therapeutic potential of activating the ACE2/Ang(1-7)/Mas receptor axis. 46,48 A novel member of the Ang peptide family, Ala 1 -Ang(1-7) (alamandine), has been isolated from human plasma and rat heart. 50,66 Alamandine is a product of decarboxylation of the N-terminal Asp residue of Ang II to form Ala, which has been demonstrated in heart, followed by hydrolysis of Ala 1 -Ang II by ACE2.…”