Role of Mitochondria in Ischemia/Reperfusion Injury and Arrhythmias

Coronary heart disease is the leading cause of death, responsible for the death of close to 380,000 out of approximately 600,000 people who die of different types of heart disease each year in the US. Coronary occlusion can cause ischemia and lead to mitochondrial and cellular injury. To decrease the ischemic damage, reperfusion is necessary. However, a more severe damage and an increased risk of potentially fatal arrhythmias are associated with reperfusion. The ischemia/reperfusion (IR)-induced oxidative stress and depolarization of mitochondrial inner-membrane potential (ΔΨ) can lead to malfunction of both the mitochondrial Ca2+ transporting system and ATP production. Preserving the mitochondrial Ca2+ handling might protect against SR Ca2+ overload, which normally would trigger delayed afterdepolarizations, and subsequently, arrhythmias. Alternatively, IR compromisation of mitochondrial ATP production can set off another arrhythmogenic mechanism through activation of sarcolemmal KATP (sarcKATP) channels, which alters the electrophysiology of cardiomyocytes in a heterogeneous manner and leads to an increased dispersion of repolarization. Coverslip-induced IR (inducing ischemia by covering cardiomyocytes with a glass coverslip placed on top of them) in monolayers of neonatal rat ventricular myocytes (NRVM) will be used as the experimental platform to determine the individual contributions of specific ion channels/transporters in IR-related arrhythmias or cell injury in a controlled manner. To precisely characterize the role of different ion channels involved in IR arrhythmias, both chemical and genetic techniques will be used. Genetic methods are especially pursued in the absence of target-specific chemical modifying agents. This project is an important step towards understanding the mechanism of the arrhythmias caused by IR and investigating antiarrhythmic interventions. (AHA Program: Postdoctoral Fellowship)