Cardiovascular diseases (CVDs) remain a leading global health threat, characterized by complex pathological mechanisms including myocardial injury, heart failure, atherosclerosis, and vascular remodeling. In recent years, peptide-based research has emerged as a promising direction in cardiovascular science, with growth hormone-releasing peptides (GHRPs) attracting increasing attention for their potential cardioprotective properties. Among these, Hexarelin and GHRP-6 stand out as two well-studied peptides, whose multifunctional roles extend beyond growth hormone (GH) secretion to exert direct and indirect regulatory effects on the cardiovascular system. This review summarizes the structural features, mechanisms of action, and current research progress of Hexarelin and GHRP-6 in cardiovascular science, highlighting their potential as therapeutic targets for CVDs.
Structural Characteristics and Classification
Hexarelin and GHRP-6 both belong to the GHRP family, a class of synthetic peptides designed to stimulate the release of endogenous growth hormone from the anterior pituitary gland. Despite their shared classification, they differ significantly in structural composition, which underlies their distinct biological activities.
Hexarelin
Hexarelin, also known as Examorelin, is a synthetic hexapeptide with the amino acid sequence His-D-2-Nal-D-Phe-Lys-NH2. Its structural feature of containing a D-2-naphthylalanine (D-2-Nal) residue enhances its stability, prolongs its half-life, and strengthens its binding affinity to the growth hormone secretagogue receptor (GHS-R), the key receptor mediating its biological effects.
GHRP-6
GHRP-6 is a hexapeptide with the sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2. Unlike Hexarelin, it contains a D-tryptophan residue, which contributes to its specific binding to GHS-R but results in a shorter half-life and lower bioavailability compared to Hexarelin, as it is more susceptible to degradation by proteases in the circulatory system.
Mechanisms of Action in the Cardiovascular System
The cardioprotective effects of Hexarelin and GHRP-6 are primarily mediated through two pathways: direct interaction with cardiac cells and indirect regulation via GH secretion. Both peptides bind to GHS-R, which is widely expressed in cardiovascular tissues, including cardiomyocytes, vascular smooth muscle cells (VSMCs), and endothelial cells, laying the foundation for their cardiovascular regulatory roles.
Direct Cardioprotective Effects
Hexarelin and GHRP-6 exert direct protective effects on cardiac cells by inhibiting apoptosis, reducing oxidative stress, and regulating myocardial remodeling.
Hexarelin has been shown to significantly inhibit cardiomyocyte apoptosis induced by angiotensin Ⅱ (Ang Ⅱ) through downregulating Bax protein expression, upregulating Bcl-2 expression, and inhibiting caspase-3 enzyme activity, thereby reducing myocardial cell loss and improving cardiac function in heart failure models. Additionally, it exhibits potent anti-myocardial hypertrophy effects by suppressing Ang Ⅱ-induced myocardial cell hypertrophy, which is associated with inhibiting AT1 receptor mRNA expression and downregulating ERK1/2 activity. In atherosclerosis models, Hexarelin also demonstrates anti-atherosclerotic properties by increasing serum HDL-C levels, reducing LDL-C levels and aortic lipid deposition, and inhibiting Ang Ⅱ-induced vascular smooth muscle cell proliferation.
GHRP-6 plays a similar role in inhibiting cardiomyocyte apoptosis, particularly in heart failure models. Studies on heart failure rats have shown that intravenous injection of GHRP-6 can improve left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), reduce left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD), and alleviate myocardial remodeling. Its anti-apoptotic mechanism involves regulating the expression of Bcl-2 and Bax proteins, increasing cholinesterase activity and cholinergic nerve density, and reducing the levels of serum cystatin C, NT-proBNP, Ang Ⅱ, and aldosterone, which are key markers of cardiac dysfunction.
Indirect Cardiovascular Regulation via GH Secretion
As GHRPs, Hexarelin and GHRP-6 indirectly regulate cardiovascular function by stimulating GH release. GH plays a crucial role in maintaining cardiac structure and function, promoting myocardial cell growth, enhancing myocardial contractility, and improving vascular endothelial function. By promoting endogenous GH secretion, both peptides indirectly exert cardioprotective effects: they enhance myocardial contractility, reduce myocardial fibrosis, and improve vascular endothelial function, thereby alleviating the progression of heart failure and atherosclerosis.
Notably, Hexarelin exhibits a stronger GH-releasing activity than GHRP-6, and its longer half-life allows for more sustained GH secretion, resulting in more durable cardioprotective effects. In contrast, GHRP-6 has a weaker GH-releasing capacity and shorter duration of action, which limits its long-term regulatory effects on the cardiovascular system.
Current Research Status and Future Perspectives
Current research on Hexarelin and GHRP-6 in cardiovascular science is mainly based on in vitro and animal experiments. Hexarelin has shown promising results in animal models of heart failure and atherosclerosis, with its multi-target cardioprotective effects making it a potential candidate for clinical translation. GHRP-6, while exhibiting certain cardioprotective properties, is limited by its short half-life and weak activity, which restricts its clinical application potential.
Future research should focus on improving the bioavailability of GHRP-6, exploring the combined application of Hexarelin with other cardioprotective peptides or therapeutic strategies, and conducting more high-quality clinical trials to verify the safety and efficacy of these peptides in human cardiovascular diseases. With the continuous development of peptide synthesis technology and cardiovascular science, Hexarelin and GHRP-6 are expected to provide new therapeutic options for the prevention and treatment of CVDs.
