Cardiac-specific overexpression of Claudin-5 exerts protection against myocardial ischemia and reperfusion injury

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2022-12, Vol.1868 (12), p.166535-166535, Article 166535
• Main Authors: Jiang, Shuai, Liu, Shuai, Hou, Yuxuan, Lu, Chenxi, Yang, Wenwen, Ji, Ting, Yang, Yang, Yu, Zhibin, Jin, Zhenxiao
• Format: Article
• Language: English
• Subjects: Claudin-5; Endoplasmic reticulum stress; Myocardial ischemia and reperfusion; Oxidative stress; SIRT1
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2022.166535

Claudin-5 has recently attracted increasing attention by its potential as a novel treatment target in the early stage of heart failure. However, whether Claudin-5 produces beneficial effects on myocardial ischemia and reperfusion (IR) injury has not been elucidated yet. In this study, we identified reduced levels of Claudin-5 in the hearts of mice subjected to acute myocardial IR injury and murine HL-1 cardiomyocytes subjected to hypoxia and reoxygenation (HR). We then constructed cardiac-specific Cldn5-overexpressing mice using an adeno-associated virus (AAV9) vector and demonstrated that Cldn5 overexpression ameliorated cardiac dysfunction and myocardial damage in mice subjected to myocardial IR injury. Moreover, Cldn5 overexpression attenuated myocardial oxidative stress (DHE and protein levels of Nrf2, HO-1, and NQO1), inflammatory response (levels of MPO, F4/80, Ly6C, and circulating inflammatory cells), mitochondrial dysfunction (protein levels of PGC-1α, NRF1, and TFAM), endoplasmic reticulum stress (protein levels of GRP78, ATF6, and CHOP and p-PERK), energy metabolism disorder (p-AMPK and ACC), and apoptosis (TUNEL assay and protein levels of Bax and Bcl2) in mice subjected to myocardial IR. Next, we generated Cldn5 knockdown cells by lentiviral shRNA and observed that Cldn5 knockdown inhibited cell viability and affected the expression or activation of these IR-related signalings in HL-1 cardiomyocytes subjected to HR. Mechanistically, SIRT1 was proved to be involved in regulating the expression of Claudin-5 by co-immunoprecipitation analysis and Sirt1 knockdown experiments. Our data demonstrated that targeting Claudin-5 may represent a promising approach for preventing and treating acute myocardial IR injury. •Claudin-5 is reduced during myocardial ischemia and reperfusion (IR) and cardiomyocyte hypoxia and reoxygenation (HR).•Cldn5 overexpression mitigates IR-induced cardiac injury and dysfunction.•Cldn5 overexpression ameliorates several IR-related pathophysiological alterations.•Cldn5 knockdown aggravates HR-induced cell injury and disruption of essential signaling pathways in HL-1 cardiomyocytes.•SIRT1 is partly involved in regulating Claudin-5 in cardiomyocytes.