Characterization of a critical role for CFTR chloride channels in cardioprotection against ischemia/ reperfusion injury  

作　　者：Sunny Yang XIANG Linda L YE Li-lu Marie DUAN Li-hui LIU Zhi-dong GE John A AUCHAMPACH Garrett J GROSS Dayue Darrel DUAN 

机构地区：[1]Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA [2]Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, W153226, USA [3]Institute of Clinical Pharmacology, Central South University Xiangya School of Medicine, Changsha 410078, China

出　　处：《Acta Pharmacologica Sinica》2011年第6期824-833,共10页中国药理学报（英文版）

摘　　要：Aim： To further characterize the functional role of cystic fibrosis transmembrane conductance regulator （CFTR） in early and late （second window） ischemic preconditioning （IPC）- and postconditioning （POC）-mediated cardioprotection against ischemia/reperfusion （I/R） injury. Methods： CFTR knockout （CFTR-/-） mice and age- and gender-matched wild-type （CFTR＋/＋） and heterozygous （CFTR＋/-） mice were used. In in vivo studies, the animals were subjected to a 30-min coronary occlusion followed by a 40-min reperfusion. In ex vivo （isolate heart） studies, a 45-min global ischemia was applied. To evaluate apoptosis, the level of activated caspase 3 and TdT-mediated dUTP-X nick end labeling （TUNEL） were examined. Results： In the in vivo I/R models, early IPC significantly reduced the myocardial infarct size in wild-type （CFTR＋/＋） （from 40.4%±5.3% to 10.4%±2.0%, n=8, P〈0.001） and heterozygous （CFTR＋/-） littermates （from 39.4%±2.4% to 15.4%~5.1%, n=6, P〈0.001） but failed to protect CFTR knockout （CFTR-/-） mice from I/R induced myocardial infarction （46.9%±6.2% vs 55.5%±7.8%, n=6, P〉0.5）. Simi- lar results were observed in the in vivo late IPC experiments. Furthermore, in both in vivo and ex vivo I/R models, POC significantly reduced myocardial infarction in wild-type mice, but not in CFTR knockout mice. In ex vivo I/R models, targeted inactivation of CFTR gene abolished the protective effects of IPC against I/R-induced apoptosis. Conclusion： These results provide compelling evidence for a critical role for CFTR Cl- channels in IPC- and POC-mediated cardioprotec- tion against I/R-induced myocardial injury.Aim： To further characterize the functional role of cystic fibrosis transmembrane conductance regulator （CFTR） in early and late （second window） ischemic preconditioning （IPC）- and postconditioning （POC）-mediated cardioprotection against ischemia/reperfusion （I/R） injury. Methods： CFTR knockout （CFTR-/-） mice and age- and gender-matched wild-type （CFTR＋/＋） and heterozygous （CFTR＋/-） mice were used. In in vivo studies, the animals were subjected to a 30-min coronary occlusion followed by a 40-min reperfusion. In ex vivo （isolate heart） studies, a 45-min global ischemia was applied. To evaluate apoptosis, the level of activated caspase 3 and TdT-mediated dUTP-X nick end labeling （TUNEL） were examined. Results： In the in vivo I/R models, early IPC significantly reduced the myocardial infarct size in wild-type （CFTR＋/＋） （from 40.4%±5.3% to 10.4%±2.0%, n=8, P〈0.001） and heterozygous （CFTR＋/-） littermates （from 39.4%±2.4% to 15.4%~5.1%, n=6, P〈0.001） but failed to protect CFTR knockout （CFTR-/-） mice from I/R induced myocardial infarction （46.9%±6.2% vs 55.5%±7.8%, n=6, P〉0.5）. Simi- lar results were observed in the in vivo late IPC experiments. Furthermore, in both in vivo and ex vivo I/R models, POC significantly reduced myocardial infarction in wild-type mice, but not in CFTR knockout mice. In ex vivo I/R models, targeted inactivation of CFTR gene abolished the protective effects of IPC against I/R-induced apoptosis. Conclusion： These results provide compelling evidence for a critical role for CFTR Cl- channels in IPC- and POC-mediated cardioprotec- tion against I/R-induced myocardial injury.

关 键 词：ISCHEMIA PRECONDITIONING POSTCONDITIONING apoptosis cystic fibrosis transmembrane conductance regulator （CFTR） 

分 类 号：Q463[生物学—生理学] Q813.3