CD36 Mediates the Cardiovascular Action of Growth Hormone-Releasing Peptides in the Heart

Abstract

Abstract-Growth hormone-releasing peptides (GHRPs) are known as potent growth hormone secretagogues whose actions are mediated by the ghrelin receptor, a G protein-coupled receptor cloned from pituitary libraries. Hexarelin, a hexapeptide of the GHRP family, has reported cardiovascular activity. To identify the molecular target mediating this activity, rat cardiac membranes were labeled with a radioactive photoactivatable derivative of hexarelin and purified using lectin affinity chromatography and preparative gel electrophoresis. A binding protein of M r 84 000 was identified. The N-terminal sequence determination of the deglycosylated protein was identical to rat CD36, a multifunctional glycoprotein, which was expressed in cardiomyocytes and microvascular endothelial cells. Activation of CD36 in perfused hearts by hexarelin was shown to elicit an increase in coronary perfusion pressure in a dose-dependent manner. This effect was lacking in hearts from CD36-null mice and hearts from spontaneous hypertensive rats genetically deficient in CD36. The coronary vasoconstrictive response correlated with expression of CD36 as assessed by immunoblotting and covalent binding with hexarelin. These data suggest that CD36 may mediate the coronary vasospasm seen in hypercholesterolemia and atherosclerosis. Key Words: acute coronary syndromes Ⅲ growth hormone-releasing peptides Ⅲ CD36 scavenger receptor G rowth hormone-releasing peptides (GHRPs) belong to a family of small synthetic peptides modeled from Metenkephalin, which exhibit potent and dose-dependent GHreleasing activity and also significant prolactin (PRL)-and corticotropin (ACTH)-releasing effects. 1 These neuroendocrine activities of GHRPs are mediated by the Ghrelin receptor, a specific G protein-coupled receptor 2,3 that has been cloned from mammalian pituitary libraries and its subtypes identified in the pituitary gland, hypothalamus, and extra-hypothalamic brain regions by binding studies. 4 Equilibrium displacement binding assays with GHRPs in different peripheral tissues have shown specific binding sites in the heart, adrenal, ovary, testis, lung, and skeletal muscle. 5,6 Significantly, hexarelin, a hexapeptide member of the GHRPs family has been reported to feature cardiovascular activity. Long-term pretreatment of GH-deficient rats with this peptide provided protective effect on hearts from ischemia/reperfusion damages 7 and prevented alterations of the vascular endothelium-dependent relaxant function. 8 This protective effect was independent of any stimulation of the somatotropic axis, 8,9 suggesting a direct action of hexarelin on specific cardiac receptors. Our initial characterization of a putative cardiac GHRP receptor revealed the existence of a binding site for a photoactivatable derivative of hexarelin with a M r of 84 000 distinct from those identified in the pituitary. 6,10 In the present study, we report the identification of the unique GHRP binding site in the heart as CD36, a multifunctional B-type scavenger receptor. We also demonstrate that t...

CD36: Implications in cardiovascular disease

“…Cross-linking experiments using hearts from CD36 KO mice showed no binding partner. In an isolated perfused heart system, hexarelin induced a dose dependent vasoconstriction that again was not observed in hearts from CD36 KO mice and spontaneous hypertensive rats (SHR), which have also been shown to lack CD36 (Bodart, et al, 2002). Detailed mapping by enzymatic and chemical degradation showed that the binding site for hexarelin overlapped with the oxLDL site and the apparent point of contact was methionine 169 (Demers, et al, 2004).…”

“…Another ligand for CD36 is the GHRP, hexarelin, and a derivative with no growth hormone releasing properties, EP 80317 (Bodart, et al, 2002). Previous work had shown that hexarelin pretreatment of growth hormone deficient rats protected against cardiac damage in ischemia/ reperfusion models.…”

Fatty acid oxidation in cardiac and skeletal muscle mitochondria is unaffected by deletion of CD36

“…Following electrophoresis in 10% Tris-HCl SDS-PAGE gels the separated proteins were transferred onto a PVDF membrane. Membranes were blocked with TBS-Tween containing 5% milk and then incubated with primary polyclonal rabbit antibodies to CD36 (1:5000) [11], followed by donkey anti-rabbit secondary antibody and development with enhanced chemiluminescence (Amersham). Bands were quantified using commercially available software.…”

La ghréline, un exemple saisissant de pléïotropie des peptides neuroendocriniens

“…Cette enzyme aurait donc pu être impliquée dans les mécanismes de désacylation de la ghréline : il ne semble pas que ce soit le cas [11]. L'hexaréline, mais pas le MK 0677 ni la ghréline, se fixe avec une affinité raisonnable au CD36, un récepteur d'épuration multifonctionnel [12]. Enfin, le (ou les) récepteur(s) relayant les effets de la ghréline non acylée reste(ent) totalement inconnus……”

“…Le CD36 est un récepteur d'épuration multifonctionnel de type B, impliqué dans l'athérogenèse et le métabolisme des lipoprotéines. Exprimé principalement par les cardiomyocytes et les cellules endothéliales de la microvasculature, le CD36 semble intervenir dans les effets cardiovasculaires sélectifs des GHS de nature peptidique [12]. Des effets de la ghréline ont également été décrits sur l'axe reproducteur (la ghréline inhibe l'activité prolifé-rative des cellules de Leydig immatures), sur les systè-mes immunitaires et ostéo-articulaires, ou encore sur le sommeil et l'anxiété [35].…”