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1 Department of Physiology, Institute of Basic Medical Sciences, Beijing, China
2 Division of Cardiology, Department of Medicine, Peking Union Hospital, Beijing, China
3 Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
4 Endocrine Cell Biology, Prince Henry's Institute of Medical Research, Melbourne, Victoria, Australia; Department of Physiology, Institute of Basic Medical Sciences, Beijing, China
* To whom correspondence should be addressed. E-mail: chen.chen{at}phimr.monash.edu.au.
Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (Ang II), an important neuro-hormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we have examined whether hexarelin can prevent cardiomyocytes from Ang II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with Ang II. Apoptosis was evaluated utilizing fluorescence microscopy, TUNEL (TdT-mediated dUTP nick end labeling) method, flow cytometry, DNA laddering and analysis of cell viability by MTT. It was found that incubation with 0.1 µmol/L Ang II for 48 hours increased cardiomyocyte apoptosis. Administration of 0.1 µmol/L hexarelin significantly decreased this Ang II -induced apoptosis and DNA fragmentation, and increased myocyte viability. To further investigate the underlying mechanisms, the caspase-3 activity assay and mRNA expression of bax, bcl-2 and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was up-regulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from Ang II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and bax expression induced by Ang II and by increasing the expression of bcl-2 which is depressed by Ang II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.
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