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

Takashi Suzuki,Teruki Sato,Yumiko Imai,Hiroshi Ito,Hiroyuki Watanabe,Keiji Kuba,Ayumi Kadowaki

doi:10.3390/ijms20020239

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.

Highlights

Apelin is an endogenous peptide ligand for dreceptor and has potent positive inotropic activity and vasodilatory action [1,2,3]
We showed that angiotensin II (Ang II)-mediated cardiac dysfunction, hypertrophy, and fibrosis were augmented in apelin knockout (Apelin KO) mice
When the mice were continuously injected with Ang II for 2 weeks, both wild type (WT) and Apelin KO mice showed elevated blood pressure in a comparable manner, and there was no difference in hypertension between the mice (Figure 1A–C)

Summary

Introduction

Apelin is an endogenous peptide ligand for dreceptor (or Aplnr) and has potent positive inotropic activity and vasodilatory action [1,2,3]. The apelin–APJ axis regulates cardiovascular functions including blood pressure, cardiac contractility, and fluid balance, and thereby exerts beneficial effects on cardiovascular systems [5,6]. Treatment with apelin peptide in vivo improves the cardiac contractility and output in myocardial infarcted rats and normal mice, and protects the heart from pressure overload, isoproterenol-induced injury, or ischemia reperfusion injury [7,8,9]. In studies of apelin knockout and APJ knockout mice, we and others have demonstrated that the endogenous apelin–APJ axis regulates the heart contractility associated with aging, exercise, and pressure overload; in the absence of apelin or APJ expression, these mutant mice show contractile dysfunctions [8,10,11]. The precise role of endogenous apelin signaling in heart function remains elusive

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