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

• Published in: European journal of pharmacology Vol. 919; p. 174801
• Main Authors: Liu, Yu, Chu, Guojun, Shen, Wenzhi, Zhang, Yuefan, Xu, Wei, Yu, Yongsheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.03.2022
• Subjects: AMP-Activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Apoptosis - drug effects; Cardiotonic Agents - chemistry; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Disease Models, Animal; Fibrosis; Inflammation; Male; Mammalian sterile 20-like kinase 1; Mice; Mice, Inbred C57BL; Mitochondrial function; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - drug effects; Signal Transduction - drug effects; Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Mammalian sterile 20-like kinase 1; Inflammation; AMP-Activated protein kinase; Mitochondrial function; Fibrosis
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2022.174801

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 AMPKα 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.