RESUMO
Myocardial ischemia is the most common cardiovascular disease. Reperfusion, an important myocardial ischemia tool, causes unexpected and irreversible damage to cardiomyocytes, resulting in myocardial ischemia/reperfusion (MI/R) injury. Upon stress, especially oxidative stress induced by reactive oxygen species (ROS), autophagy, which degrades the intracellular energy storage to produce metabolites that are recycled into metabolic pathways to buffer metabolic stress, is initiated during myocardial ischemia and MI/R injury. Excellent cardioprotective effects of autophagy regulators against MI and MI/R have been reported. Reversing disordered cardiac metabolism induced by ROS also exhibits cardioprotective action in patients with myocardial ischemia. Herein, we review current knowledge on the crosstalk between ROS, cardiac autophagy, and metabolism in myocardial ischemia and MI/R. Finally, we discuss the possible regulators of autophagy and metabolism that can be exploited to harness the therapeutic potential of cardiac metabolism and autophagy in the diagnosis and treatment of myocardial ischemia and MI/R.
RESUMO
Myocardial infarction (MI) is irreversible damage caused by ischemia and hypoxia in coronary arteries accompanied by elevated catecholamine levels, leading to the accumulation of free radicals. Our previous study discovered coumarin-derived imino sulfonates as a novel class of potential cardioprotective agents possessing strong anti-oxidative effects in cardiomyocytes. Therefore, identifying the compound with the highest cardioprotective activity, 5h, and the mechanism involved was necessary. As a kind of catecholamine, isoproterenol can clinically induce myocardial infarction injury similar to the symptoms of myocardial infarction patients. Our experiments explored the underlying mechanism of this effect of compound 5h by assessing cardiac function, infarct size, histopathological changes, and downregulation of Sirt1 by transfection of adenovirus in vitro and by administering Ex527, a specific inhibitor of Sirt1, in vivo. Compound 5h exhibited strong cardioprotective actions in vivo and in vitro via improving cell survival and cardiac function and decreasing the cellular oxidative stress and cardiac infarct size against MI. Furthermore, compound 5h significantly enhanced cardiac expression of Sirt1, subsequently activating the Nrf2/NQO1 signaling pathway. However, adenovirus-induced Sirt1 downregulation or Sirt1-specific inhibitor largely blocked such beneficial effects of 5h in vitro and in vivo, respectively. Taken together, our results demonstrated, for the first time, that the cardioprotective action of 5h against MI was mediated by reducing oxidative stress and apoptosis through the Sirt1/Nrf2 signaling pathway. Our findings proposed novel insights in developing and evaluating coumarin-derived imino sulfonate compounds as epigenetics-targeted drug therapy for MI.
