Apelin is a positive regulator of ACE2 in failing hearts

Abstract

Angiotensin converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system (RAS), catalyzing the conversion of Angiotensin II to Angiotensin 1-7. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardioprotective peptide. While an antagonistic relationship between the RAS and apelin has been proposed, such functional interplay remains elusive. Here we found that ACE2 was downregulated in apelin-deficient mice. Pharmacological or genetic inhibition of angiotensin II type 1 receptor (AT1R) rescued the impaired contractility and hypertrophy of apelin mutant mice, which was accompanied by restored ACE2 levels. Importantly, treatment with angiotensin 1-7 rescued hypertrophy and heart dysfunctions of apelin-knockout mice. Moreover, apelin, via activation of its receptor, APJ, increased ACE2 promoter activity in vitro and upregulated ACE2 expression in failing hearts in vivo. Apelin treatment also increased cardiac contractility and ACE2 levels in AT1R-deficient mice. These data demonstrate that ACE2 couples the RAS to the apelin system, adding a conceptual framework for the apelin-ACE2-angiotensin 1-7 axis as a therapeutic target for cardiovascular diseases.

Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction

“…Gene expression analysis was next performed in isolated LECs from ischemic Activated cardiac LECs express apelin and its receptor APJ. Despite a well-established role of apelin in the regulation of cardiac contractility and angiogenesis (18)(19)(20), its role in cardiac lymphatic endothelium has to the best of our knowledge never been explored. To address this issue, we first analyzed by RT-qPCR the expression of Apln (apelin) as well as its receptor APJ in the ischemic area 2 days, 1 week, and 1 month after MI ( Figure 3, A and B).…”

Effects of apelin on the cardiovascular system

“…The apelin/APJ system acts as a counterregulator of the renin-angiotensin system (RAS), in which a central role is played by Ang II. Two signalling mechanisms are involved in this antagonism: 1) the interaction between AT1 and APJ modulates the function of these receptors [28], and 2) the negative regulation of RAS by angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin converting enzyme (ACE) [29,30]. [24,25].…”

“…Unlike ACE, ACE2 is a negative regulator of RAS because it is responsible for the conversion of Ang II to Ang 1-7. The importance of apelin in ACE2 activation results from the observation that the latter is downregulated in apelin-deficient mice [30]. However, treatment with Ang 1-7 limits myocardial dysfunction, hypertrophy and fibrosis [30,34], as well as endothelial dysfunction [35].…”

“…The importance of apelin in ACE2 activation results from the observation that the latter is downregulated in apelin-deficient mice [30]. However, treatment with Ang 1-7 limits myocardial dysfunction, hypertrophy and fibrosis [30,34], as well as endothelial dysfunction [35]. Thus, it was thought that the axis apelin-ACE2-Ang 1-7 represents a signalling protective pathway and that angiotensin 1-7 does not simply indicate Ang II removal, but it also displays a therapeutic effect via its own G-protein coupled receptor, Mas, associated with cardiac protective responses [30].…”

“…However, treatment with Ang 1-7 limits myocardial dysfunction, hypertrophy and fibrosis [30,34], as well as endothelial dysfunction [35]. Thus, it was thought that the axis apelin-ACE2-Ang 1-7 represents a signalling protective pathway and that angiotensin 1-7 does not simply indicate Ang II removal, but it also displays a therapeutic effect via its own G-protein coupled receptor, Mas, associated with cardiac protective responses [30]. ACE2 counteracts RAS also by transforming Ang I into Ang 1-9 by the hydrolysis of the carboxy terminal leucine [36,37] (Fig.…”