Hexarelin, a synthetic growth hormone-releasing peptide, binds to and triggers the growth hormone secretagogue receptor (GHSR) in the brain like its natural analog ghrelin. However, the peripheral distribution of GHSR in the heart and blood vessels suggests that hexarelin might influence cardiovascular functions directly.

The non-GHSR CD36 further acts as a specific cardiac receptor for hexarelin. It exhibits greater stability and potency compared to ghrelin and thus holds promise as a cardiovascular therapeutic agent. The cardiac action of hexarelin was reported to be mediated in part by GHSR 1a and largely by activation of the CD36 receptor in isolated working hearts. In this concise review, we discuss the current evidence for the cardiovascular action of hexarelin.

1. Cardiovascular Action of Hexarelin

1.1. Inotropic effect
Acute intravenous use of hexarelin had a short-lasting, positive inotropic effect. Hexarelin administration increased LVEF, cardiac output, and cardiac index while decreasing the wedge pressure.

1.2. Inhibition of apoptosis
Hexarelin significantly decreased angiotensin II-induced apoptosis and DNA fragmentation and increased myocyte viability in neonatal rat cardiomyocytes. It further inhibited doxorubicin-induced apoptosis and promoted the survival of H9c2 cardiomyocytes and endothelial cells. Chronic administration of hexarelin thus inhibits stress-induced neurohormonal activation and cardiomyocyte apoptosis.

1.3. Ischemia-reperfusion injury
Hexarelin treatment protected the electrophysiological properties of cardiomyocytes after ischemia-reperfusion injury and inhibited cardiomyocyte apoptosis and promoted cell survival by modifying mitogen-activated protein kinase pathways and produced a positive inotropic effect on ischemic cardiomyocytes.

The chronic administration of the peptide to GH-deficient rats protected against ischemic and post-ischemic ventricular dysfunction and prevented hyper-responsiveness of the coronary vascular bed to angiotensin II in perfused hearts.

1.4. Myocardial infarction
Compared with normal saline, hexarelin treatment was found to increase stroke volume, stroke volume index, cardiac output, and cardiac index and decreased total peripheral resistance.

1.5. Cardiac fibrosis
The treatment of spontaneously hypertensive rats significantly decreased cardiac fibrosis by reducing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing collagen I and III mRNA and protein expression.

In addition, hexarelin treatment increased matrix metalloproteinase-2 and -9 activities and reduced myocardial mRNA expression of the tissue inhibitor of metalloproteinase-1.

1.6. Atherosclerosis
The anti-atherosclerotic activity of the peptide was observed in adult Sprague-Dawley rats. Treatment with the peptide suppressed atherosclerotic plaques and neointima formation, partially reversed serum high-density lipoprotein cholesterol/low-density lipoprotein cholesterol ratio, and improved serum nitric oxide levels and aortic mRNA expression of endothelial nitric oxide synthase, GHSRs, and CD36 in atherosclerotic rats.

Furthermore, chronic treatment with hexarelin unaltered the high triglyceride levels and significantly decreased plasma cholesterol concentrations in obese rats.

2. Hexarelin Activates the Cardiac Receptor

The cardiovascular action of hexarelin has been regarded as GH-independent and occurs through activation of cardiac receptors. The peptide significantly increased LVEF in normal and in GH-deficient patients and prevented cardiac damage after ischemia-reperfusion in hypophysectomized rats indicating that its cardioprotective activity is not due to stimulation of the GH axis.

Hexarelin can bind to targeted cardiac sites. Specific 125I-Tyr-Ala-hexarelin binding was observed in the human cardiovascular system, and the highest 125I-Tyr-Ala-hexarelin levels were detected in the ventricles, followed by atria aorta, coronaries, carotid, endocardium, and vena cava. Currently, two cardiac receptor subtypes have been proposed for hexarelin.

2.1. Cardiac GHSR 1a receptor
The peptide induced expression of GHSR mRNA expression in cardiomyocytes. Further, hexarelin significantly prolonged action potential duration produced positive inotropic effects and preserved electrophysiological properties after ischemia-reperfusion injury in isolated myocytes. These effects were found to be mediated by the GHSR 1a receptor.

2.2. Cardiac CD36 receptor
CD36, a multifunctional glycoprotein expressed in cardiomyocytes and microvascular endothelial cells, serves as a specific receptor for the peptide. Hexarelin-mediated activation of CD36 in perfused hearts increased coronary perfusion pressure in a dose-dependent manner.

This effect was not observed in hearts from CD36-null mice and from spontaneously hypertensive rats genetically deficient in CD36.

3. Hexarelin vs. Ghrelin

Hexarelin has more potent beneficial effects on the cardiovascular system compared with its natural analog ghrelin. However, other studies reported that when GHSR 1a activation was identical, hexarelin and ghrelin had similar cardiac effects, although the dosage of ghrelin was ten times higher than that of hexarelin in molar terms.

Research also showed that ghrelin- and hexarelin-mediated activation of GHSR 1a had a similar protective effect on cardiomyocytes after ischemia-reperfusion injury by inhibiting cardiomyocyte apoptosis and promoting cell survival.

4. Conclusions

Hexarelin has cardioprotective activity in common cardiovascular conditions such as cardiac fibrosis, ischemic heart disease, cardiac dysfunction, and atherosclerosis which seem to be mediated through the direct binding and activation of its cardiac receptors CD36 and GHSR 1a.

Since hexarelin is a chemically stable synthetic GHS with more potent cardiac effects than its natural analog ghrelin, it can be a potential alternative to ghrelin as a promising therapeutic agent for the treatment of cardiovascular diseases. However, prima facie evidence is obtained from animal and cell line studies. Hence clinical trials in human subjects are necessary for the establishment of its efficacy.



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