KPC1 alleviates hypoxia/reoxygenation-induced apoptosis in rat cardiomyocyte cells though BAX degradation
KPC1 alleviates hypoxia/reoxygenation-induced apoptosis in rat cardiomyocyte cells though BAX degradation
复制标题
KPC1 通过 BAX 降解减轻缺氧/复氧诱导的大鼠心肌细胞凋亡
DOI：
10.1002/jcp.28854
复制
发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Tang, Jun-Ming
中科院分区：
文献类型：
--
作者：
Yuan, Ye;Wang, Yong-yi;Tang, Jun-Ming
Bax通过使线粒体外膜透化，导致膜电位损失和细胞色素c释放来触发细胞凋亡。然而，目前尚不清楚蛋白酶体降解Bax是否参与凋亡过程，特别是在心脏缺血再灌注（I/R）诱导的损伤。在本研究中，KPC 1的表达在冠心病（CHD）患者的左心室心肌细胞，在I/R心肌在体内和缺氧和复氧（H/R）诱导的心肌细胞在体外增加。过表达KPC 1可减少I/R大鼠心肌梗死面积和细胞凋亡。类似地，KPC 1的强制表达恢复了H9c2细胞中由H/R驱动的线粒体膜电位（MMP）和细胞色素c释放，而减少了细胞凋亡，并且通过短发夹RNA（shRNA）敲低KPC 1恶化了H/R诱导的细胞凋亡。从机制上讲，强制表达KPC 1促进Bax蛋白降解，蛋白酶体抑制剂MG 132可消除这种作用，表明KPC 1促进Bax的蛋白酶体降解。此外，KPC 1可以阻止基础和细胞凋亡应激诱导的Bax向线粒体的移位。Bax可能是KPC 1对I/R诱导的心肌细胞凋亡的抗凋亡作用的新靶点，并使KPC 1的线粒体效应的至少一个子集机械渗透。
Bax triggers cell apoptosis by permeabilizing the outer mitochondrial membrane, leading to membrane potential loss and cytochrome c release. However, it is unclear if proteasomal degradation of Bax is involved in the apoptotic process, especially in heart ischemia-reperfusion (I/R)-induced injury. In the present study, KPC1 expression was heightened in left ventricular cardiomyocytes of patients with coronary heart disease (CHD), in I/R-myocardium in vivo and in hypoxia and reoxygenation (H/R)-induced cardiomyocytes in vitro. Overexpression of KPC1 reduced infarction size and cell apoptosis in I/R rat hearts. Similarly, the forced expression of KPC1 restored mitochondrial membrane potential (MMP) and cytochrome c release driven by H/R in H9c2 cells, whereas reducing cell apoptosis, and knockdown of KPC1 by short-hairpin RNA (shRNA) deteriorated cell apoptosis induced by H/R. Mechanistically, forced expression of KPC1 promoted Bax protein degradation, which was abolished by proteasome inhibitor MG132, suggesting that KPC1 promoted proteasomal degradation of Bax. Furthermore, KPC1 prevented basal and apoptotic stress-induced Bax translocation to mitochondria. Bax can be a novel target for the antiapoptotic effects of KPC1 on I/R-induced cardiomyocyte apoptosis and render mechanistic penetration into at least a subset of the mitochondrial effects of KPC1.