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

被引:20
作者
Liu, Yu [1 ]
Chu, Guojun [2 ]
Shen, Wenzhi [1 ]
Zhang, Yuefan [3 ]
Xu, Wei [1 ]
Yu, Yongsheng [3 ]
机构
[1] Nanjing Univ, Med Sch, Affiliated Nanjing Drum Tower Hosp, Dept Cardiol, Nanjing 210008, Peoples R China
[2] Navy Mil Med Univ, Changhai Hosp, Dept Cardiovasol, Shanghai, Peoples R China
[3] Shanghai Univ, Sch Med, Shangda Rd 99, Shanghai 200444, Peoples R China
基金
中国国家自然科学基金;
关键词
Mammalian sterile 20-like kinase 1; Mitochondrial function; Inflammation; Fibrosis; AMP-Activated protein kinase; ISCHEMIA-REPERFUSION INJURY; PERMEABILITY TRANSITION PORE; MITOCHONDRIAL; AMPK; ACTIVATION; MITOPHAGY; APOPTOSIS; DISEASE;
D O I
10.1016/j.ejphar.2022.174801
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页数:9
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