Cardioprotective Effects of Ghrelin in Heart Failure: From Gut to Heart

Abstract

Chronic heart failure (CHF) is a major cause of morbidity and mortality. Cardioprotective effects of ghrelin, especially in its acylated form have been demonstrated in heart failure (HF) models and exploratory human clinical studies. Hence, it has been proposed for the treatment of HF. However, the underlying mechanism of its protective effects against HF remains unclear. Future researches are needed to evaluate the efficacy of Ghrelin as a new biomarker and prognostic tool and for exploring its therapeutic potential in patients suffering from CHF.

INTRODUCTION

Chronic heart failure (CHF) is a major cause of morbidity and mortality. Apart from the many causes of CHF, a slow reduction in the number of cardiomyocytes is one of the most important causative factors.[1] Therefore, inhibiting cardiomyocyte apoptosis may have implications for the treatment of heart failure (HF).

Ghrelin

Ghrelin, a gut-derived 28-amino acid peptide hormone was first identified in 1999 by Kojima as an endogenous ligand for the GH secretagogue receptor (GHS-R), an endogenous stimulator of GH and is now implicated in a number of physiological processes. Cardioprotective effects of ghrelin, especially in its acylated form have been demonstrated on HF models and exploratory human clinical studies. Hence, it has been proposed for the treatment of HF. However, the underlying mechanism of its protective effects against HF remains unclear.

Cardiovascular Effects of Ghrelin

Clinical studies have reported that ghrelin confers a variety of potentially beneficial cardiovascular effects, which includes reduction of mean arterial blood pressure, increase in myocardial contractility, protection of endothelial cells, and improvement of energy metabolism of myocardial cells.[2,3] Exogenous administration of ghrelin also results in improvement in coronary flow, heart rate, dilatation of peripheral blood vessels, constriction of coronary arteries, and improvement in ventricular and endothelial function. Clinical studies have reported that exogenous administration of ghrelin decreases muscle wasting, improves exercise capacity, inhibits cardiomyocyte apoptosis, inhibits sympathetic nerve activity, and protects from HF induced by myocardial infarction.[4,5,6] Importantly, administration of ghrelin has been demonstrated to improve the cardiac function and prognosis in patients suffering from end-stage CHF.[7] In vitro, ghrelin decreases inotropism and lusitropism. Ghrelin reverses cardiac cachexia by promoting a positive energy balance and also by enhancing direct cardioprotective effects of ghrelin.[8] These cardioprotective effects are independent of growth hormone release and likely involve binding to cardiovascular receptors.[9]

There is a widespread distribution of ghrelin and its receptors (GHSR 1a) in the cardiovascular tissues, which provides a definitive evidence of its cardiac actions. The protective effects of ghrelin on heart are mediated through direct effects on the heart and blood vessel and through its growth-hormone-releasing effect. In normal individuals, acute increases in ghrelin do not alter cardiac metabolism, whereas in patients with HF, they enhance oxidation of free fatty acids and reduce the oxidation of glucose, thus partly correcting its metabolic alterations. This interesting mechanism of action of ghrelin may contribute to the cardioprotective effects of ghrelin in HF.[10]

Ghrelin mediates cardioprotective effects by modulating cardiac autonomic nervous activity. However; the precise mechanisms by which ghrelin regulates sympathetic activity are still unclear and needs further investigation. Peripheral ghrelin may act on GHSR 1a at the cardiac vagal nerve ending, which goes to the nucleus of tractus solitarius (NTS) and inhibit the renal sympathetic nerve activity (SNA).[11] Ghrelin can also act directly on the central nervous system (CNS) and alter the sensitivity of CNS to other hormones participating in regulation of sympathetic activity.[12] Administration of ghrelin brings down the plasma levels of epinephrine and dopamine and shifts the balance of autonomic nervous activity toward parasympathetic nervous activity.[11]

Ghrelin increases the size of cardiomyocytes, prolongs their survival, and protects the cardiomyocytes against apoptosis and myocardial injury induced by endoplasmic reticulum stress (ERS) through a GHS-R1a, calmodulin-dependent protein kinase kinase (CaMKK), and adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway.[13] Administration of ghrelin lowers the release of lactate dehydrogenase (LDH) and myoglobin by the cardiomyocytes, indicating protection against cardiomyocyte injury. So also, ghrelin may have other cardiovascular beneficial effects in the form of prevention of atherosclerosis as well as protection from ischemia and reperfusion injury.

Levels of Angiotensin II (Ang II) and ghrelin are both significantly increased in patients with HF.[14] Ghrelin inhibits cardiomyocyte apoptosis both in vivo and in vitro. Ghrelin inhibits the Ang II induced cardiomyocyte apoptosis in patients with HF. Ghrelin also inhibits the AT1 receptor up-regulation induced by Ang II, thereby playing a role in preventing HF.[14] Elevated levels of ghrelin in patients with HF can be a protective compensatory mechanism for reduced body weight in order to enhance appetite and weight gain in cachexia patients with HF. However, Chang et al. has reported that plasma ghrelin levels are significantly lower in patients with HF and also differ with the severity of HF and that higher levels of ghrelin is an indicator of a better prognosis for HF.[15] Thus; ghrelin can be considered as a new biomarker of severity as well as prognostic predictor for patients with CHF.

CONCLUSION

The multifunctional nature of ghrelin makes it an interesting pharmacological target for various diseases. Future researches are needed to evaluate the efficacy of ghrelin as a new biomarker and prognostic tool and for exploring its therapeutic potential in patients suffering from CHF.