Inhibition of GPR35 Preserves Mitochondrial Function After Myocardial Infarction by Targeting Calpain 1/2
Inhibition of GPR35 Preserves Mitochondrial Function After Myocardial Infarction by Targeting Calpain 1/2
复制标题
通过靶向钙蛋白酶抑制 GPR35 可保留心肌梗塞后的线粒体功能 1/2
DOI：
10.1097/fjc.0000000000000819
复制
发表时间：
2020-06-01
影响因子：
3
通讯作者：
Yang, Dachun
中科院分区：
文献类型：
--
作者：
Chen, Ken;He, Lei;Yang, Dachun
缺血和缺氧引起的线粒体损伤可能是导致心肌梗死（MI）时心脏损伤的关键因素。钙蛋白酶1和钙蛋白酶2参与了心肌梗死诱导的线粒体损伤。缺氧可触发G蛋白偶联受体35 （GPR35）。GPR35是否调控calpain1 /2参与心肌梗死的发病机制尚不清楚。在本研究中，我们确定心肌梗死增加了心肌组织中GPR35的表达。抑制GPR35通过降低活性氧活性和线粒体依赖性凋亡来保护小鼠心肌损伤。进一步研究表明GPR35调控calpain 1/2。抑制GPR35可降低calpain 1/2的表达和活性，减轻calpain 1/2相关的线粒体损伤，维持心功能。基于这些数据，我们得出结论，GPR35的功能性抑制下调了calpain 1/2，并有助于线粒体疾病病理条件下心脏功能的维持。总之，我们的研究表明，GPR35对calpain 1/2的调控在心肌梗死的发病机制中具有重要意义。靶向GPR35和calpain 1/2在线粒体中的作用为心肌梗死的治疗提供了潜在的干预措施。
Ischemia and anoxia-induced mitochondrial impairment may be a key factor leading to heart injury during myocardial infarction (MI). Calpain 1 and 2 are involved in the MI-induced mitochondria injury. G protein-coupled receptor 35 (GPR35) could be triggered by hypoxia. Whether or not GPR35 regulates calpain 1/2 in the pathogenesis of MI is still unclear. In this study, we determined that MI increases GPR35 expression in myocardial tissue. Suppression of GPR35 protects heart from MI injury in mice through reduction of reactive oxygen species activity and mitochondria-dependent apoptosis. Further studies show that GPR35 regulates calpain 1/2. Suppression of GPR35 reduces the expression and activity of calpain 1/2, and alleviates calpain 1/2-associated mitochondrial injury to preserve cardiac function. Based on these data, we conclude that a functional inhibition of GPR35 downregulates calpain 1/2 and contributes to maintenance of cardiac function under pathologic conditions with mitochondrial disorder. In conclusion, our study showed that the identified regulation by GPR35 of calpain 1/2 has important implications for the pathogenesis of MI. Targeting the action of GPR35 and calpain 1/2 in mitochondria presents a potential therapeutic intervention for MI.