Hexarelin protects H9c2 cardiomyocytes from doxorubicin-induced cell death

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules that possess strong growth hormone-releasing activity acting on s pecific pituitary and hypothalamic receptor subtypes, Differently from nonp eptidyl GHSs, peptidyl molecules such as hexarelin, a hexapeptide, possess specific high-affinity binding sites in animal and human heart and, after p rolonged treatment, protect rats in vivo from ischemia-induced myocardial d amage. To verify the hypothesis that peptidyl GHSs protect heart cells from cell death, we have investigated the cellular effects of hexarelin on H9c2 cardiomyocytes, a fetal cardiomyocyte-derived cell line, and on Hend, an e ndothelial cell line derived from transformed murine heart endothelium. We show that (i) H9c2 cardiomyocytes show specific binding for I-125-Tyr-Ala-h exarelin, which is inhibited by peptidyl GHSs such as Tyr-Ala-hexarelin and hexarelin but not by the nonpeptidyl GHS MK-0677, (ii) hexarelin promotes survival of H9c2 cardiomyocytes induced to die by doxorubicin, and (iii) th at hexarelin inhibits apoptosis, as measured by DNA fragmentation, induced in both H9c2 myocytes and endothelial cells. In conclusion, our findings sh ow that peptidyl GHSs such as hexarelin act as survival factors for cardiom yocytes and endothelium-derived cells in culture. These findings suggest th at the inhibitory activity of hexarelin on cardiomyocytes and endothelial c ell death could explain, at least partially, its cardioprotective effect ag ainst ischemia recorded in rats in vivo.