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1 Laboratoire de Genomique Fonctionnelle, CNRS, UPR 2580, Montpellier, France
2 Cardiology Division, University Hospital, Montpellier, France
3 CHU A de Villeneuve, INSERM U637, Montpellier, France
4 Cardiology Division, University Hospital, Montpellier, France; CHU A de Villeneuve, INSERM U637, Montpellier, France
* To whom correspondence should be addressed. E-mail: c-piot{at}chu-montpellier.fr.
Morphine has cardioprotective effects against ischemic-reperfusion injuries. This study investigates whether morphine could mimic the anti-apoptotic effect of preconditioning using a model of cultured neonatal rat cardiomyocytes subjected to metabolic inhibition (MI). To quantify MI-induced apoptosis, DNA fragmentation and mitochondrial cytochrome c release levels were measured by ELISA. MI-dependent DNA fragmentation was prevented by both Z-VAD-fmk (20 µM), a pan-caspase inhibitor, and cyclosporine A (CsA, 5 µM), a mitochondrial pore transition blocker, added during MI (36% and 54% decrease, respectively). MI-dependent cytochrome c release was not blocked by Z-VAD-fmk, but was decreased (38%) by CsA during MI. Metabolic preconditioning (MIP) and preconditioning with morphine (1 µM) were also assessed. MI-dependent DNA fragmentation and cytochrome c release were prevented by MIP (40% and 45% decrease, respectively) and morphine (34% and 45%, respectively). The anti-apoptotic effect of morphine was abolished by naloxone (10 nM), a non-selective opioid receptor antagonist, or xestospongin C (XeC, 400 nM), an inhibitor of inositol (1,4,5) trisphosphate (IP3)-mediated calcium (Ca2+) release. Ca2+ preconditioning, induced by increasing extracellular Ca2+ from 1.8 to 3.3 mM, mimicked the anti-apoptotic effect of morphine on DNA fragmentation (24% decrease) and cytochrome c release (57% decrease). This effect mediated by extracellular Ca2+ was also abolished by XeC. Measurements of intracellular Ca2+ ([Ca2+]i) using fura-2 microspectrofluorimetry showed that morphine induces IP3-dependent Ca2+ transients abolished by 2-aminoethoxydiphenyl borate (2-APB), a cell-permeable IP3 antagonist. These results suggest that morphine preconditioning prevents simulated ischemia/reperfusion-induced apoptosis via an IP3-signaling pathway in rat ventricular myocytes.
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