Hexarelin, a synthetic growth hormone-releasing peptide, appears to bind to and trigger the brain’s growth hormone secretagogue receptor (GHSR) like its natural analog ghrelin. However, the peripheral distribution of GHSR in the heart and blood vessels suggests that Hexarelin may influence cardiovascular functions directly.
The non-GHSR CD36 further acts as a specific cardiac receptor for Hexarelin. Researchers have reported that it exhibits greater stability and potency compared to ghrelin and thus may hold 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 research on the cardiovascular action of Hexarelin.
1. Potential Cardiovascular Action of Hexarelin
1.1. Inotropic effect
Researchers have reported acute administration of Hexarelin to induce a short-lasting, positive inotropic effect. Hexarelin administration was reported to increase LVEF, cardiac output, and cardiac index while decreasing the wedge pressure.
1.2. Inhibition of apoptosis
Hexarelin may significantly decrease angiotensin II-induced apoptosis and DNA fragmentation and increase myocyte viability in neonatal rat cardiomyocytes. It further has the potential to inhibit doxorubicin-induced apoptosis and promote the survival of H9c2 cardiomyocytes and endothelial cells. Chronic administration of Hexarelin thus may inhibit stress-induced neurohormonal activation and cardiomyocyte apoptosis.
1.3. Ischemia-reperfusion injury
Researchers reported that Hexarelin had the potential to enhance cardiomyocytes’ electrophysiological properties after ischemia-reperfusion injury, inhibit cardiomyocyte apoptosis, and promote cell survival by modifying mitogen-activated protein kinase pathways. Finally, studies suggested its potential to produce a positive inotropic effect on ischemic cardiomyocytes.
The chronic administration of the peptide to GH-deficient rats in laboratory experiments was observed to protect 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 appeared to have the potential to increase stroke volume, stroke volume index, cardiac output, cardiac index, and decrease total peripheral resistance. This potential was reported across multiple research studies.
1.5. Cardiac fibrosis
The treatment of spontaneously hypertensive rats was reported to significantly decrease 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 was suggested by researchers to increase matrix metalloproteinase-2 and -9 activities and reduce myocardial mRNA expression of the tissue inhibitor of metalloproteinase-1.
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 was reported to unalter the high triglyceride levels and significantly decrease plasma cholesterol concentrations in obese rats. Further studies are required to validate the peptide’s mechanism of action.
2. Hexarelin and the Cardiac Receptor
Studies have suggested the potential cardiovascular action of Hexarelin has to be GH-independent and occurs through the activation of cardiac receptors. The peptide appeared to increase LVEF in normal and in GH-deficient patients. It also appeared to prevent cardiac damage after ischemia-reperfusion in hypophysectomized rats indicating that its potential cardioprotective activity is not due to stimulation of the GH axis.
Hexarelin may potentially 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 was reported to have the potential to induce expression of GHSR mRNA expression in cardiomyocytes. Further, Hexarelin appeared to significantly prolong action potential duration producing positive inotropic effects and preserving electrophysiological properties after ischemia-reperfusion injury in isolated myocytes. This potential was 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 or spontaneously hypertensive rats genetically deficient in CD36. Further research is required to validate the peptide’s potential.
3. Hexarelin vs. Ghrelin
Hexarelin has been suggested by some researchers have more potent effects on the cardiovascular system than its natural analog Ghrelin. However, other studies reported that when GHSR 1a activation was identical, Hexarelin and Ghrelin exhibited similar cardiac effects in the lab setting, although the dosage of ghrelin was ten times higher than that of Hexarelin in molar terms.
Research also suggested that Ghrelin- and Hexarelin- mediated activation of GHSR 1a exhibited a similar possible protective effect on cardiomyocytes after ischemia-reperfusion injury by inhibiting cardiomyocyte apoptosis and promoting cell survival.
Hexarelin has the potential to induce 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 potentially more potent cardiac effects than its natural analog ghrelin, it may be a potential alternative to ghrelin as a promising therapeutic agent for treating cardiovascular diseases. However, prima facie support 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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Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.