XMU-MP-1 protects heart from ischemia/reperfusion injury in mice through modulating Mst1/AMPK pathway

Up to now, there are few therapeutic approaches available to protect heart from ischemia/reperfusion (I/R) injury. The present work was designed to examine the protection of XMU-MP-1, an inhibitor of mammalian sterile 20-like kinase 1 (Mst1), against myocardial I/R injury in mice and investigate the underlying molecular mechanisms. The wild-type and Mst1 (-/-) mice were exposed to I/R injury and treated with XMU-MP-1 immediately after reperfusion. Treatment with XMU-MP-1 reduced infarct size, attenuated apoptosis and necrosis, and preserved cardiac function of I/R mice. XMU-MP-1 mitigated mitochondrial dysfunction in myocardium of I/R mice. In addition, XMU-MP-1 stimulated M2 macrophage polarization and suppressed inflammation in myocardium of I/R mice. Mst1 deficiency had similar benefits on myocardial I/R injury and XMU-MP-1 treatment did not provide further protection against I/R injury in Mst1 (-/-) mice. Both treatment with XMU-MP-1 and Mst1 deficiency promoted the activation of AMPK alpha in myocardium of I/R mice. More importantly, administration of Compound C (a specific AMPK signaling blocker) blunted the protective effects of XMU-MP-1 on myocardial I/R injury. Collectively, reperfusion therapy with XMU-MP-1 mitigated myocardial I/R injury and preserved myocardial function in mice through modulating Mst1/AMPK pathway.