A Novel Role of Claudin-5 in Prevention of Mitochondrial Fission Against Ischemic/Hypoxic Stress in Cardiomyocytes.
A Novel Role of Claudin-5 in Prevention of Mitochondrial Fission Against Ischemic/Hypoxic Stress in Cardiomyocytes.
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DOI：
10.1016/j.cjca.2021.03.021
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Kim JK
中科院分区：
文献类型：
--
作者：
Luo T;Liu H;Chen B;Liu H;Abdel-Latif A;Kitakaze M;Wang X;Wu Y;Chou D;Kim JK
Downregulation of claudin-5 in the heart is associated with the end-stage heart failure. However, the underlying mechanism of claudin-5 is unclear. Here we investigated the molecular actions of claudin-5 in perspective of mitochondria in cardiomyocytes to better understand the role of claudin-5 in cardioprotection during ischemia. Claudin-5 was detected in the murine heart tissue and the neonatal rat cardiomyocytes (NRCM). Its protein level was severely decreased after myocardial ischemia/reperfusion (I/R; 30 min/24 h) or hypoxia/reoxygenation (H/R; 24 h/4 h). Claudin-5 was present in the mitochondria of NRCM as determined by confocal microscopy. H/R-induced downregulation of claudin-5 was accompanied by mitochondrial fragmentation. The protein level of mitofusin 2 (Mfn2) was dramatically decreased while the expression of dynamin-related protein (Drp) 1 was significantly increased after H/R. H/R-induced mitochondrial swelling and fission were observed by transmission electron microscope (TEM). Overexpression of claudin-5 by adenoviral infection reversed these structural disintegration of mitochondria. The mitochondria-centered intrinsic pathway of apoptosis triggered by H/R and indicated by the expression of cytochrome c and cleaved caspase 3 in the cytoplasm of NRCMs was also reduced by overexpressing claudin-5. Overexpression of claudin-5 in mouse heart also significantly decreased cleaved caspase 3 expression and the infarct size in ischemic heart with improved systolic function. We demonstrated for the first time the presence of claudin-5 in the mitochondria in cardiomyocytes and provided the firm evidence for the cardioprotective role of claudin-5 in the preservation of mitochondrial dynamics and cell fate against hypoxia- or ischemia-induced stress. Claudin-5 is known as a tight junction protein controlling the endothelial permeability. It was found expressed in cardiomyocyte’s mitochondria and its expression was dramatically decreased along with mitochondiral fission after ischemia/reperfusion (I/R) injury. Overexpression of claudin-5 in cardiomyocytes prevented mitochondial fission and apoptosis and improved heart function after myocardial I/R. The present findings may improve our current understanding of the role of claudin-5 in the cell and provide new theraputic target for ischemic heart disease.
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影响因子：
11.1
作者：
Dorn GW 2nd
通讯作者：
Dorn GW 2nd
抑制动力相关蛋白 1 可预防糖尿病小鼠心肌缺血再灌注损伤
影响因子：
9.3
作者：
Ding M;Dong Q;Liu Z;Liu Z;Qu Y;Li X;Huo C;Jia X;Fu F;Wang X
通讯作者：
Wang X
影响因子：
4.8
作者：
D'Souza, T;Agarwal, R;Morin, PJ
通讯作者：
Morin, PJ
影响因子：
5.3
作者：
Huang, Ping;Zhou, Chang-Man;Han, Jing-Yan
通讯作者：
Han, Jing-Yan
影响因子：
5
作者：
Mays, Tessily A.;Binkley, Philip F.;Rafael-Fortney, Jill A.
通讯作者：
Rafael-Fortney, Jill A.