Mechanisms of Ghrelin Anti-Heart Failure: Inhibition of Ang II-Induced Cardiomyocyte Apoptosis by Down-Regulating AT1R Expression

Chunyan Yang,Kai Liu,Zhonghui Liu,Ping Yang,Rajesh Gopalrao Katare

doi:10.1371/journal.pone.0085785

Abstract

BackgroundGhrelin is a novel growth hormone–releasing peptide administered to treat chronic heart failure (CHF). However, the underlying mechanism of its protective effects against heart failure (HF) remains unclear.Methods and ResultsA total of 68 patients with CHF and 20 healthy individuals were included. The serum levels of Angiotensin II (Ang II) and ghrelin were measured using ELISA. The results showed that Ang II and ghrelin were both significantly increased in CHF patients and that the ghrelin levels were significantly positively correlated with Ang II. The left anterior descending coronary artery was ligated to establish a rat model of CHF, and cultured cardiomyocytes from neonatal rats were stimulated with Ang II to explore the role of ghrelin in CHF. The results showed that ghrelin inhibited cardiomyocyte apoptosis both in vivo and in vitro. Furthermore, caspase-3 expression was examined, and the results revealed that Ang II induces cardiomyocyte apoptosis through the caspase-3 pathway, whereas ghrelin inhibits this action. Lastly, to further elucidate the mechanism by which ghrelin inhibits Ang II action, the expression of the AT1 and AT2 receptors was evaluated; the results showed that Ang II up-regulates the AT1 and AT2 receptors in cardiomyocytes, whereas ghrelin inhibits AT1 receptor up-regulation but does not affect AT2 receptor expression.ConclusionsThese data suggest that the serum levels of ghrelin are significantly positively correlated with Ang II in CHF patients and that ghrelin can inhibit Ang II-induced cardiomyocyte apoptosis by down-regulating AT1R, thereby playing a role in preventing HF.

Highlights

Chronic heart failure (CHF) is the ultimate outcome of most cardiovascular diseases and is a major cause of disability and death in cardiovascular disease patients [1,2]
These data suggest that the serum levels of ghrelin are significantly positively correlated with angiotensin II (Ang II) in chronic heart failure (CHF) patients and that ghrelin can inhibit Ang II-induced cardiomyocyte apoptosis by down-regulating AT1R, thereby playing a role in preventing HF
Ghrelin and Ang II were upregulated in patients with CHF, and ghrelin levels were positively correlated with Ang II

Summary

Introduction

Chronic heart failure (CHF) is the ultimate outcome of most cardiovascular diseases and is a major cause of disability and death in cardiovascular disease patients [1,2]. CHF has many causes, a gradual decrease in cardiomyocyte number is one of the most important contributing factors [3,4]. Increasing evidence indicates that one of the important forms of cardiomyocyte loss during CHF is cardiomyocyte apoptosis, which can be lethal even at very low levels [5,6,7]. Limiting cardiac muscle loss by inhibiting cardiomyocyte apoptosis may have implications for heart failure (HF) treatment. Experimental studies of HF in animal models and patients suggest that the cardiac renin-angiotensin system (RAS) is activated and that angiotensin II (Ang II) production is enhanced [8]. The underlying mechanism of its protective effects against heart failure (HF) remains unclear

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