CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart
Bodart V, Febbraio M, Demers A, McNicoll N, Pohankova P, Perreault A, Sejlitz T, Escher E, +3 more
Circulation Research (2002)
A radioactive photoactivatable hexarelin derivative cross-linked to an 84-kDa cardiac membrane protein identified by sequencing as CD36 — and the hexarelin coronary-perfusion-pressure effect was abolished in CD36-null mice and in CD36-deficient spontaneously hypertensive rats. The molecular identification of hexarelin's cardiac receptor.
This is the foundational mechanism paper for hexarelin's cardiac receptor, published in Circulation Research in 2002 by Bodart, Ong, and colleagues at the Université de Montréal in collaboration with Maria Febbraio and Roy Silverstein (then at Weill-Cornell). The paper uses a photoaffinity cross-linking strategy to identify the cardiac binding protein for hexarelin — a growth hormone-releasing peptide (GHRP-6 derivative) whose cardiovascular effects had been characterized in clinical and preclinical work through the late 1990s but whose cardiac binding partner had not been molecularly identified at that point.
The methodology is direct. A radioactive (¹²⁵I) photoactivatable hexarelin derivative was synthesized and incubated with rat cardiac membrane preparations, then UV-cross-linked to the binding partner. Affinity-purified cross-linked complexes were resolved by SDS-PAGE, the 84-kDa band was excised, and protein sequencing identified the binding partner as CD36 — a class B scavenger receptor previously characterized as a thrombospondin-, oxidized-LDL-, and long-chain-fatty-acid-binding glycoprotein. The functional confirmation used two genetic models: hexarelin failed to elicit its characteristic increase in coronary perfusion pressure in CD36-null mouse hearts and in CD36-deficient spontaneously hypertensive rat hearts. In CD36-competent rat hearts, hexarelin produced a dose-dependent increase in coronary perfusion pressure that was abolished in the CD36-deficient comparators. The paper concluded that CD36 is the functional cardiac target of hexarelin's cardiovascular activity — distinct from the GHSR-1a pituitary receptor that mediates the GH-release effect.
This is the mechanistic anchor that makes hexarelin pharmacologically distinct from every other peptide in the growth-hormone-secretagogue class. Ipamorelin and the other selective GHSR-1a agonists do not engage CD36 at meaningful affinity; the cardiac literature on hexarelin (acute LVEF effects in healthy volunteers, cardioprotection in hypophysectomized rats incapable of producing GH, infarct-size reduction in ischemia-reperfusion models) is mechanistically anchored to the CD36 binding rather than to the GH-release pathway. The CD36 entry in the peptide receptor pharmacology atlas rests on this paper, and the hexarelin peptide page treats the cardiac biology in the context this mechanism paper enables.
The receptor-identification experiments are technically rigorous but were conducted in rat cardiac membranes and confirmed in genetic-deficient rodent models rather than in human cardiac tissue. CD36 is a broadly expressed scavenger receptor with multiple endogenous ligands (thrombospondin-1, oxidized LDL, long-chain fatty acids, Plasmodium-infected erythrocytes); the receptor's role in hexarelin's pharmacology is one binding interaction among many, and the broader physiology of CD36 (fatty-acid uptake in cardiomyocytes and adipocytes, microvascular signaling, malarial pathology) is the context in which the hexarelin interaction sits. The coronary-perfusion-pressure effect characterized in the paper is one functional cardiac readout; the full clinical-relevance breadth of CD36-mediated hexarelin pharmacology — particularly chronic-exposure cardiac remodeling and ischemia-reperfusion protection — was characterized in subsequent papers from related groups but never produced regulator-grade trial-scale data. The hexarelin cardiac development program was commercially abandoned in part because the tachyphylaxis curve and pituitary spillover (large cortisol, prolactin, ACTH responses with chronic dosing) limited the clinical-development thesis at scale; CD36 binding identified hexarelin's most distinctive cardiac biology but did not produce a marketable cardiac indication. The paper's molecular-evidence strength is high; the trial-evidence depth around the molecule it characterizes is comparatively limited. The /peptides/hexarelin page covers the broader development trajectory and the resulting gap between molecular-mechanism depth and clinical-trial depth that the hexarelin literature exhibits.
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