Mechanism Of Energy Metabolism In The Pathogenesis Of Myocardial Microcirculation Ischemia Reperfusion Injury And Heart Failure

Background:Reperfusion therapy is the main treatment method for acute myocardial infarction at present,but reperfusion injury limits the clinical benefit of patients and increases the incidence of heart failure.From reperfusion injury to the different stages of heart failure,various cells(including microcirculatory endothelial cells and cardiomyocytes)play a role.Our previous studies have confirmed that microcirculation damage caused by reperfusion injury is the most important link in the occurrence of reperfusion injury,and the damage of microcirculation will further aggravate the hypoxia injury of myocardial cells,and eventually cause the necrosis and fibrosis of myocardial cells,leading to the occurrence of heart failure.Therefore,in order to significantly improve the prognosis of patients and reduce the occurrence of heart failure,it is necessary to elucidate the injury mechanism of different cells at different stages.Mitochondria are the core of cell energy metabolism,providing essential energy for life activities.Our study has confirmed the role of mitochondrial injury and changes in cell energy metabolism in the progression of reperfusion injury and heart failure.But the upstream signals that cause mitochondrial damage and regulate changes in mitochondrial metabolism are not clear.Therefore,it is of great significance to explore the damage mechanism of microcirculation endothelial cells and myocardial cells in acute and chronic myocardial injury during reperfusion injury for improving the prognosis of patients with myocardial infarction.Aim:The main purpose of this study is through the mitochondrial damage and mitochondrial energy metabolism,explore in microcirculation reperfusion damage endothelial cells and mitochondria in long-term anoxic environment damage and mitochondrial energy metabolism changes mechanism,clarify microcirculation damage as well as the mechanism of myocardial injury,to seek effective prediction strategy and improve the prognosis of patients.Methods:qPCR,western blots,co-immunoprecipitation,immunofluorescence,adenovirus-mediated gene overexpression,mutant plasmid transfection were used to evaluate the transcription and expression of protein,mitochondrial energy metabolism and mitochondrial ROS generation and mitochondrial cyt-c release,mitochondrial membrane potential,mPTP opening,mitochondrial apoptotic pathways,mitochondrial respiratory chain complex enzymes changes.Results:1.Oxidative stress injury induced IP3R-dependent[Ca2+]c overload that contributed to CMECs apoptosis.2.IP3R-dependent[Ca2+]c overload activated VDAC-mediated[Ca2+]m overload that caused mitochondrial structural and functional destroy.3.MAPK/ERK was activated by melatonin and contributed to the protective effects of melatonin on CMECs under H202.4.Expressions of miR-138 in cardiac cells are modulated by hypoxia.5.MiR-138 inhibits glycolysis and promotes mitochondrial respiration.6.PDK1 is a direct target of miR-138.7.Hypoxia suppresses cardiac cells viability through increased glycolysis and decreased mitochondrial respiration.8.Overexpression of miR-138 increases the cardiac cells viability through targeting PDK1 under hypoxia.Conclusions:1.Calcium functions as the transmitter that elevated by IP3R and permeates widely into mitochondria via VDAC,causing mitochondria calcium overload which is responsible for the collapse of mitochondrial structure and function.2.Melatonin could stimulate MAPK/ERK that inactive CREB and downregulate IP3R/VDAC expression,contributing to the[Ca2+]c/[Ca2+]m homeostasis and stopping mitochondrial-dependent death pathways.3.MiR-138 expressions were significantly suppressed under long exposure to hypoxia and overexpression of miR-138 protects human cardiac cells against hypoxia.4.MiR-138 inhibits glycolysis but promotes mitochondrial respiration through direct targeting PDK1.5.Hypoxia induces cardiac cell death through increased glycolysis and decreased mitochondrial respiration.6.Inhibition of glycolysis by either glycolysis inhibitor or knockdown glycolysis enzymes,Glutl or PDK1 contributes to cardiac cells survival.7.Restoration of PDK1 in miR-138 overexpressing cardiac cells recovers cell sensitivity to hypoxia.