Characterization of a critical role for CFTR chloride channels in cardioprotection against ischemia/ reperfusion 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 （CFT...

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Published in:	Acta pharmacologica Sinica 2011-06, Vol.32 (6), p.824-833
Main Authors:	Xiang, Sunny Yang, Ye, Linda L, Duan, Li-lu Marie, Liu, Li-hui, Ge, Zhi-dong, Auchampach, John A, Gross, Garrett J, Duan, Dayue Darrel
Format:	Article
Language:	eng
Subjects:	Animals Apoptosis caspase Caspase 3 - metabolism Cystic Fibrosis Transmembrane Conductance Regulator - genetics Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Cystic Fibrosis Transmembrane Conductance Regulator - physiology Disease Models, Animal Ischemic Postconditioning Ischemic Preconditioning, Myocardial Male Mice Mice, Inbred CFTR Mice, Knockout Myocardial Reperfusion Injury - metabolism Myocardial Reperfusion Injury - pathology Myocardial Reperfusion Injury - prevention & control Myocardium - metabolism Myocardium - pathology Original Perfusion 体内实验基因敲除心肌梗死氯离子通道细胞凋亡缺血/再灌注损伤表征
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Summary:	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.
ISSN:	1671-4083 1745-7254