Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling

Abstract

Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1-7-dependent manner. Whether apelin antagonizes the over-activation of the renin-angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-β) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-β expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling. Int. J. Mol. Sci. 2019, 20, 239 2 of 12dysfunctions [8,10,11]. By contrast, APJ was identified as a dual receptor to mediate cardiac hypertrophy [12,13] via β-arrestin signaling [14,15]. Thus, the precise role of endogenous apelin signaling in heart function remains elusive.Cardiac hypertrophy is an adaptive response to maintain cardiac function in the event of an increased workload, although prolonged cardiac hypertrophy can lead to heart failure via the ischemia of cardiomyocytes [16,17]. In addition, cardiac fibrosis adversely increases tissue stiffness and impairs ventricular function. Consistently, cardiac hypertrophy and the development of fibrosis correlate with the deterioration of myocardial function in heart failure [18][19][20]. Thus, cardiac hypertrophy and fibrosis are key features of heart failure, and apelin's inotropic and protective roles in the heart are attractive as a potential therapeutic candidate for treating heart failure.Apelin has also been identified as a substrate for angiotensin-converting enzyme 2 (ACE2), which cleaves apelin with similar efficiency as its primary substrate angiotensin II (Ang II) [21][22][23]. ACE2 is a negative regulator of the renin-angiotensin system (RAS) that inactivates Ang II by converting it to angiotensin 1-7 (Ang 1-7) [21][22][23], whereas angiotensin-converting enzyme 1 (or ACE1) activates RAS by converting Ang I to Ang II. ACE2 was also identified as a regulator of heart failure [24-26], diabetic nephropathy [27,28], acute lung failure [29,30], and the SARS (severe acute respiratory syndrome) coronavirus receptor [31,32].Apelin-APJ sig...

Angiotensin (1–7) and Apelin co-therapy: New strategy for heart failure treatment of rats

“…Injury with myocardial ischemia, such as myocardial LDH leakage and lipid peroxidation (MDA), has been significantly reduced. Pathological reactions during the development of HF include myocyte hypertrophy and cardiac fibrosis, which is strongly influenced by Ang II signaling ( 15 ). Apelin has been shown to decrease Ang II-induced cardiac dysfunction and pathological remodeling and to antagonize endogenous Ang II-mediated heart contractility impairment in mice ( 15 ).…”

“…Considering the above, 1) there is a partial improvement of cardiac function by Ang (1–7) and apelin, 2) there is a reduction in the apelin levels during HF, and 3) apelin induces angiotensin-converting enzyme 2 (ACE2) to improve the heart function in Ang (1–7) manner ( 15 ), and thus we assumed that combined administration of apelin and Ang (1–7) would have more beneficial effects than the administration of either of these agents alone.…”

The Role of Secretory Activity Molecules of Visceral Adipocytes in Abdominal Obesity in the Development of Cardiovascular Disease: A Review

“…Plasma levels of apelin are substantially lower in patients with atrial fibrillation than in healthy subjects. There are data on a higher risk of repeated atrial fibrillation in subjects with a lower level of apelin [101,102]. The level of apelin starts to decline early after AMI.…”

The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders

“…Downregulation of the apelin pathway action lowers ACE2 levels, leading to the activation of the renin–angiotensin system (Fig. ) . Indeed, the deletion of apelin in mice leads to cardiac dysfunction, which is abrogated by blockade of the AT1 receptor or using AT1 receptor KO mice .…”