Cardiac ischemia/reperfusion injury is associated with reduced mitochondrial turnover and regeneration. There is currently no effective approach to stimulate mitochondrial biogenesis in the reperfused myocardium. In this study, we investigated whether melatonin could increase mitochondrial biogenesis and thus promote mitochondrial homeostasis in cardiomyocytes. Cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) injury with or without melatonin treatment, and various mitochondrial functions were measured. H/R injury repressed mitochondrial biogenesis in cardiomyocytes, whereas melatonin treatment restored mitochondrial biogenesis through the 5' adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) pathway. Melatonin enhanced mitochondrial metabolism, inhibited mitochondrial oxidative stress, induced mitochondrial fusion and prevented mitochondrial apoptosis in cardiomyocytes subjected to H/R injury. The melatonin-induced improvement in mitochondrial biogenesis was associated with increased cardiomyocyte survival during H/R injury. On the other hand, silencing of PGC1α attenuated the protective effects of melatonin on cardiomyocyte viability, thereby impairing mitochondrial bioenergetics, disrupting the mitochondrial morphology, and activating mitochondrial apoptosis. Thus, H/R injury suppressed mitochondrial biogenesis, while melatonin activated the AMPK/PGC1α pathway and restored mitochondrial biogenesis, ultimately protecting the reperfused heart.
Pre-clinical evaluation of cardiac dysfunction is important for assessing the safety of traditional or novel medicines due to the universality of potential drug-induced heart failure and irreversible arrhythmia. Aconitine (ACO), a traditionally used anti-pyretic, analgesic and anti-rheumatic drug, has been reported to have arrhythmogenic effects. In the present study, the Real-Time Cellular Analysis Cardio system was applied to evaluate the arrhythmogenic effects of ACO in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The results indicated that ACO is capable of increasing the frequency and decreasing the amplitude of hiPSC-CM contraction in a dose- and time-dependent manner. ACO at 0.25 µM increased the beating rate of hiPSC-CMs by 3.7-fold within 30 min, while 3.0 µM of ACO increased the beating rate by 7.3-fold. The present study also evaluated the potential pro-apoptotic effects of ACO by using caspase-3 and caspase-9 kits. To the best of our knowledge, the present study was the first to record the ACO-induced cardiac arrhythmia of hiPSC-CMsin real-time. The results also indicate that ACO-induced cell death is mediated, at least in part, by caspase-dependent apoptotic pathways.
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