Empagliflozin attenuates ischemia and reperfusion injury through LKB1/AMPK signaling pathway

The beneficial effects of empagliflozin (EMPA) on cardiac functions during ischemia and reperfusion were characterized. The contractile functions of isolated cardiomyocytes from adult C57BL/6J mice were determined with IonOptix SoftEdgeMyoCam system. The mitochondrial superoxide production was measured by MitoSOX fluorescent probe. The ex vivo isolated heart perfusion system was used to determine the pharmacological effects of EMPA on heart's contractile functions under both physiological and pathological conditions. The in vivo regional myocardial ischemia and reperfusion by ligation of left artery coronary artery descending (LAD) was used to measure the myocardial infarction caused by ischemia and reperfusion with or without EMPA treatment. The results demonstrated that EMPA treatment significantly improves cardiomyocyte contractility under hypoxia conditions and augments the post-ischemic recovery in the ex vivo heart perfusion system. Furthermore, the in vivo myocardial infarction measurement shows that EMPA treatment significantly reduce myocardial infarct size caused by ischemia and reperfusion. The biochemical analysis demonstrated that EMPA can trigger cardiac AMPK signaling pathway and attenuate mitochondrial superoxide production under hypoxia and reoxygenation conditions. In conclusion, EMPA can trigger AMPK signaling pathways and modulate myocardial contractility and reduce myocardial infarct size caused by ischemia and reperfusion independent of hypoglycemic effect. The results for the first time demonstrate that the activation of AMPK by EMPA could one reason about EMPA's beneficial effects on heart disease.