TRPM2 Channels Protect Hearts from Ischemia-Reperfusion Injury

TRPM2 channels are expressed in the heart and vasculature. To elucidate the function of TRPM2, we generated a global TRPM2-KO mouse. To evaluate whether TRPM2 channels were functional in the heart, we activated TRPM2 channels with H2O2 and demonstrated that Ca2+ influx was dependent on extracellular Ca2+ and significantly higher in WT compared to TRPM2-KO myocytes. We then examined the effects of TRPM2 channels on cardiac function, both at rest and after ischemia-reperfusion (I/R) injury. At rest, there were no differences in LV mass, heart rate, fractional shortening (FS) and +dP/dt between WT and TRPM2-KO hearts. At 2-3 days post-I/R injury, despite similar areas-at-risk and infarct sizes, TRPM2-KO hearts had lower FS and +dP/dt when compared to WT hearts. Compared to WT I/R myocytes, expression of Na+/Ca2+ exchanger (NCX1) and NCX1 current were increased, and action potential duration was prolonged in TRPM2-KO I/R myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation to simulate I/R in vitro, levels of reactive oxygen species (ROS) were significantly higher in TRPM2-KO when compared to WT myocytes. Oxygen radical scavenging enzymes (SOD1 and SOD2) and their upstream regulators (FoxO1, FoxO3a and HIF-1α) were lower while NADPH oxidase (Nox2) was higher in TRPM2-KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by enhancing expression of oxygen radical scavenging enzymes, thereby reducing oxidative stress associated with ischemia-reperfusion.