Protective Role of Cardiac CFTR Activation Upon Early Reperfusion Against Myocardial Infarction

Cellular Physiology and Biochemistry

关键词: CFTR;    Anion channel;    Ischemia;    Reperfusion;    Myocardial infarction;    Necrosis;   

DOI  :  10.1159/000341479

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background The cardiac isoform of the cystic fibrosis transmembrane conductance regulator (CFTR) was shown to be activated by β-adrenergic or purinergic stimulation and involved in cell volume regulation after osmotic swelling. Also, cardiac CFTR was reported to be essential in the mechanism by which ischemic preconditioning protects against ischemia/reperfusion(I/ R)-induced injury of the heart. Here, we explored the possibility that activation of cardiac CFTR can provide protection against I/R-induced myocardial infarction, even after ischemic attack. Methods The hearts of wild-type mice were subjected to 30- or 40-min left coronary artery occlusion followed by 2-h or 2-day reperfusion in vivo, and myocardial infarction was examined under a variety of conditions. Neonetal rat ventricular myocytes in primary culture were subjected to hypoxia/reoxygenation in vitro, and necrotic cell death was examined. Results The infarct size was much greater in CFTR knockout mice than in wild-type mice. Intravenous infusion of a number of putative CFTR activators upon reperfusion prominently reduced the size of myocardial infarction in wild-type but not CFTR-deficient mice. This protective effect was abolished by co-administration of a CFTR inhibitor. CFTR activators ameliorated, in a manner sensitive to a CFTR inhibitor, release of myocardial-specific creatine kinase isoenzyme to the serum in mice subjected to I/R in vivo. Necrotic death of cultured neonatal rat ventricular myocytes subjected to hypoxia/reoxygenation in vitro was ameliorated by CFTR activators or CFTR gene overexpression but aggravated by a CFTR inhibitor or CFTR gene silencing. Conclusion It is concluded that activation of endogenous myocardial CFTR upon early reperfusion is involved in protection against necrotic myocardial injury induced by I/R in vivo and in vitro. Cardiac CFTR may serve as a target accessible even after ischemic attack for pharmacotherapeutic intervention in I/R-induced myocardial infarction.

【 授权许可】

CC BY-NC-ND