Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure

Abstract

Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.

Keywords: angiotensin 1–7; angiotensin II; angiotensin-converting enzyme 2; heart failure; renin-angiotensin system.

Figure 1. The enzymatic cascade of the RAS, key receptor systems, and the biological effects mediated by Ang II and Ang 1–7

(A) The RAS cascade showing the angiotensin peptide metabolic pathway. Angiotensinogen, as the starting substrate, is cleaved by renin to Ang I. Ang I is cleaved by ACE to Ang II, which is cleaved by ACE2 to Ang 1–7. Ang II acts on AT₁ and AT₂ receptors. Ang 1–7 acts on Mas receptors and counterbalances the Ang II/AT₁R actions. (B) Decreased ACE2 shifts the balance in the RAS to the Ang II/AT₁R axis, resulting in disease progression. Increased ACE2 (by rhACE2, gene delivery, or ACE2 activators) shifts the balance to the Ang 1–7/MasR axis, leading to protection from disease.

Figure 2. Transcriptional, post-transcriptional, and post-translational regulation of ACE2

ACE2 expression is transcriptionally regulated by energy stress and activation of AMPK via SIRT1, which binds to the promoter region and facilitates ACE2 mRNA expression. Similarly, apelin binds to the promoter region of ACE2 and enhances its expression. ACE2 mRNA is subject to post-transcriptional regulation by miR-421, which regulates protein expression. Ang II, the main effector peptide of the RAS, is produced by ACE and chymase in the heart and other tissues. ACE2, a monocarboxypeptidase, degrades Ang II into a heptapetide, Ang 1–7. Ang II, via its action on AT₁R, promotes NOX2-dependent ROS formation. This leads to phosphorylation and activation of p38-MAPK and ultimately results in TACE phosphorylation (Thr735) and activation. Activated TACE proteolytically cleaves ACE2 and releases the active ACE2 ectodomain.

Figure 3. Cardiac effects of the Ang II/AT₁R axis and counter-regulation by the ACE2/Ang 1–7/MasR axis

ACE-mediated generation of Ang II results in activation of various signaling pathways in cardiomyocytes, cardiac fibroblasts, and endothelial cells, resulting in adverse cardiac remodeling and cardiac dysfunction. Activation of the ACE2/Ang 1–7/MasR axis counter-regulates Ang II/AT₁R mediated effects and also stimulates cardiac contractility mediated by the PI3K-Akt-eNOS pathway.

Figure 4. Central role of the ACE2/Ang 1–7 axis in HF: non-ischemic cardiomyopathy, MI, diabetic cardiomyopathy, and obesity-associated cardiac dysfunction

Ang II/AT₁R is critically involved in the disease progression leading to non-ischemic, ischemic, and diabetic cardiomyopathy and to obesity-associated cardiac dysfunction. By converting Ang II to Ang 1–7, ACE2 shifts the balance to the cardioprotective ACE2/Ang 1–7/MasR axis. EAT: epicardial adipose tissue.