Abstract
Background: Downregulation of claudin-5 in the heart is associated with the end-stage heart failure. However, the underlying mechanism ofclaudin-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. Methods: Myocardial ischemia/reperfusion (I/R; 30 min/24 h) and hypoxia/reoxygenation (H/R; 24 h/4 h) were used in this study. Confocal microscopy and transmission electron microscope (TEM) were used to observe mitochondrial morphology. Results: Claudin-5 was detected in murine heart tissue and neonatal rat cardiomyocytes (NRCM). Its protein level was severely decreased after myocardial I/R or H/R. Confocal microscopy showedclaudin-5 presented in the mitochondria of NRCM. H/R-induced claudin-5 downregulation was accompanied by mitochondrial fragmentation. The mitofusin 2 (Mfn2) expressionwas dramatically decreased while the dynamin-related protein (Drp) 1 expression was significantly increased after H/R. The TEM indicatedH/R-induced mitochondrial swelling and fission. Adenoviral claudin-5 overexpression reversed these structural disintegration of mitochondria. The mitochondria-centered intrinsic pathway of apoptosis triggered by H/R and indicated by the cytochrome c and cleaved caspase 3 in the cytoplasm of NRCMs was also reduced by overexpressing claudin-5. Claudin-5 overexpression in mouse heart also significantly decreased cleaved caspase 3 and the infarct size in ischemic heart with improved systolic function. Conclusion: 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1593-1606 |
| Number of pages | 14 |
| Journal | Canadian Journal of Cardiology |
| Volume | 37 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2021 |
Bibliographical note
Funding Information:This work was supported by a grant from the National Natural Science Foundation of China (grant no. 82060045 to Dr Luo), 2 Funded Projects from Zunyi Medical University (grant no. [2018]5772-025 to Dr Luo and [2018]5772-026 to Dr Chou), a grant from Guizhou province of China (grant no. [2021]224 to Dr Luo), 2 grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01 HL111180 to Dr Kim and R01 HL138488 to Dr Abdel-Latif), and a grant from the University of Kentucky COBRE Early Career Program (P20 GM103527 to Dr Abdel-Latif).
Publisher Copyright:
© 2021 Canadian Cardiovascular Society
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine