hexarelin and Heart-Failure

Ischemic and nonischemic cardiomyopathies are associated with significant morbidity and mortality in industrialized countries. Cardiomyopathies of primary origin, and more specifically the dilated form of the disease, have been associated with a number of gene defects in cytoskeletal, membrane, and sarcomeric proteins. Cardiomyopathies of secondary origin such as ischemic cardiomyopathy remain the leading cause of left ventricular systolic dysfunction and heart failure. Among novel strategies to improve cardiac function in heart failure, treatment with growth hormone, insulin growth factor-1 (IGF-1), and natural and synthetic growth hormone-releasing peptides such as ghrelin and hexarelin have been explored. The present review focuses on the issues involved in the use of exogenous growth hormone and its releasing peptides in experimental animal models of chronic heart failure and in clinical studies on cardiomyopathic patients as potential releasing peptides for the treatment of chronic heart failure developing as a consequence of cardiomyopathy.

Topics: Animals; Cardiomyopathies; Ghrelin; Growth Hormone; Growth Hormone-Releasing Hormone; Heart Failure; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Models, Animal; Myocardium; Oligopeptides; Peptide Hormones

Hexarelin is a synthetic growth hormone-releasing peptide that exerts cardioprotective effects. However, its cardioprotective effect against heart failure (HF) is yet to be explained. This study investigated the therapeutic role of hexarelin and the mechanisms underlying its cardioprotective effects against coronary artery ligation (CAL)-induced HF in rats.. Rats with four weeks of permanent CAL, induced myocardial infarction, and HF were randomly separated into four groups: the control group (Ctrl), sham group (Sham), hexarelin treatment group (HF + Hx), and heart failure group (HF). The rats were treated with subcutaneous injection of hexarelin (100 μg/kg) in the treatment group or saline in the other groups twice a day for 30 days. Left ventricular (LV) function, oxidative stress, apoptosis, molecular analyses, and cardiac structural and pathological changes in rats were assessed.. The treatment of HF rats with hexarelin significantly induced the upregulation of phosphatase and tensin homologue (PTEN) expression and inhibited the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) to significantly improve LV function, ameliorate myocardial remodeling, and reduce oxidative stress.. These findings indicate that hexarelin attenuates CAL-induced HF in rats by ameliorating myocardial remodeling, LV dysfunction, and oxidative stress via the upmodulation of PTEN signaling and downregulation of the Akt/mTOR signaling pathway.

Topics: Animals; Coronary Vessels; Disease Models, Animal; Heart Failure; Heart Ventricles; Male; Oligopeptides; PTEN Phosphohydrolase; Rats; Rats, Sprague-Dawley; Up-Regulation

Growth hormone (GH)-releasing peptides (GHRP), a class of synthetic peptidyl GH secretagogues, have been reported to exert a cardioprotective effect on cardiac ischemia. However, whether GHRP have a beneficial effect on chronic heart failure (CHF) is unclear, and the present work aims to clarify this issue. At 9 wk after pressure-overload CHF was created by abdominal aortic banding in rats, one of four variants of GHRP (GHRP-1, -2, and -6 and hexarelin, 100 mug/kg) or saline was injected subcutaneously twice a day for 3 wk. Echocardiography and cardiac catheterization were performed to monitor cardiac function and obtain blood samples for hormone assay. GHRP treatment significantly improved left ventricular (LV) function and remodeling in CHF rats, as indicated by increased LV ejection fraction, LV end-systolic pressure, and diastolic posterior wall thickness and decreased LV end-diastolic pressure and LV end-diastolic dimension. GHRP also significantly alleviated development of cardiac cachexia, as shown by increases in body weight and tibial length in CHF rats. Plasma CA, renin, ANG II, aldosterone, endothelin-1, and atrial natriuretic peptide were significantly elevated in CHF rats but were significantly decreased in GHRP-treated CHF rats. GHRP suppressed cardiomyocyte apoptosis and increased cardiac GH secretagogue receptor mRNA expression in CHF rats. GHRP also decreased myocardial creatine kinase release in hypophysectomized rats subjected to acute myocardial ischemia. We conclude that chronic administration of GHRP alleviates LV dysfunction, pathological remodeling, and cardiac cachexia in CHF rats, at least in part by suppressing stress-induced neurohormonal activations and cardiomyocyte apoptosis.

Topics: Animals; Apoptosis; Blood Pressure; Cachexia; Catecholamines; Creatine Kinase; Heart Failure; Hypophysectomy; Myocardial Ischemia; Myocytes, Cardiac; Oligopeptides; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Ghrelin; RNA, Messenger; Ventricular Dysfunction, Left; Ventricular Remodeling