Trimetazidine protects cardiomyocytes against hypoxia-induced injury through ameliorates calcium homeostasis

• Trimetazidine protects cardiomyocytes from hypoxia-induced injury.
• Trimetazidine exerted amelioration calcium homeostasis in hypoxic cardiomyocytes.
• Trimetazidine improved myocardial energy metabolism in hypoxic cardiomyocytes.

Intracellular calcium (Ca2+i) overload induced by chronic hypoxia alters Ca2+i homeostasis, which plays an important role on mediating myocardial injury. We tested the hypothesis that treatment with trimetazidine (TMZ) would improve Ca2+i handling in hypoxic myocardial injury. Cardiomyocytes isolated from neonatal Sprague–Dawley rats were exposed to chronic hypoxia (1% O2, 5% CO2, 37 °C). Intracellular calcium concentration ([Ca2+]i) was measured with Fura-2/AM. Perfusion of cardiomyocytes with a high concentration of caffeine (10 mM) was carried out to verify the function of the cardiac Na+/Ca2+ exchanger (NCX) and the activity of sarco(endo)-plasmic reticulum Ca2+-ATPase (SERCA2a). For TMZ-treated cardiomyocytes exposured in hypoxia, we observed a decrease in mRNA expression of proapoptotic Bax, caspase-3 activation and enhanced expression of anti-apoptotic Bcl-2. The cardiomyocyte hypertrophy were also alleviated in hypoxic cardiomyocyte treated with TMZ. Moreover, we found that TMZ treatment cardiomyocytes enhanced “metabolic shift” from lipid oxidation to glucose oxidation. Compared with hypoxic cardiomyocyte, the diastolic [Ca2+]i was decreased, the amplitude of Ca2+i oscillations and sarcoplasmic reticulum Ca2+ load were recovered, the activities of ryanodine receptor 2 (RyR2), NCX and SERCA2a were increased in cardiomyocytes treated with TMZ. TMZ attenuated abnormal changes of RyR2 and SERCA2a genes in hypoxic cardiomyocytes. In addition, cholinergic signaling are involved in hypoxic stress and the cardioprotective effects of TMZ. These results suggest that TMZ ameliorates Ca2+i homeostasis through switch of lipid to glucose metabolism, thereby producing the cardioprotective effect and reduction in hypoxic cardiomyocytes damage.