Structural apelin analogues: mitochondrial ROS inhibition and cardiometabolic protection in myocardial ischaemia reperfusion injury

Background and Purpose Mitochondria‐derived oxidative stress is believed to be crucially involved in cardiac ischaemia reperfusion ( I / R ) injury, although currently no therapies exist that specifically target mitochondrial reactive oxygen species ( ROS ) production. The present study was designed to evaluate the potential effects of the structural analogues of apelin‐12, an adipocyte‐derived peptide, on mitochondrial ROS generation, cardiomyocyte apoptosis, and metabolic and functional recovery to myocardial I / R injury. Experimental Approach In cultured H 9 C 2 cardiomyoblasts and adult cardiomyocytes, oxidative stress was induced by hypoxia reoxygenation. Isolated rat hearts were subjected to 35 min of global ischaemia and 30 min of reperfusion. Apelin‐12, apelin‐13 and structural apelin‐12 analogues, AI and AII , were infused during 5 min prior to ischaemia. Key Results In cardiac cells, mitochondrial ROS production was inhibited by the structural analogues of apelin, AI and AII , in comparison with the natural peptides, apelin‐12 and apelin‐13. Treatment of cardiomyocytes with AI and AII decreased cell apoptosis concentration‐dependently. In a rat model of I / R injury, pre‐ischaemic infusion of AI and AII markedly reduced ROS formation in the myocardial effluent and attenuated cell membrane damage. Prevention of oxidative damage by AI and AII was associated with the improvement of functional and metabolic recovery after I / R in the heart. Conclusions and Implications These data provide the evidence for the potential of the structural apelin analogues in selective reduction of mitochondrial ROS generation and myocardial apoptosis and form the basis for a promising therapeutic strategy in the treatment of oxidative stress‐related heart disease.