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

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

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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). Similar 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 cardioprotection against I/R-induced myocardial injury.

Original languageEnglish (US)
Pages (from-to)824-833
Number of pages10
JournalActa Pharmacologica Sinica
Volume32
Issue number6
DOIs
StatePublished - Jun 2011

Keywords

  • apoptosis
  • cystic fibrosis transmembrane conductance regulator (CFTR)
  • ischemia
  • postconditioning
  • preconditioning

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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