title: Characterization of a critical role for CFTR chloride channels in cardioprotection against ischemia/reperfusion injury.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Sunny Yang
authors.initials: SY
authors.lastname: Xiang
authors.forename: Linda L
authors.initials: LL
authors.lastname: Ye
authors.forename: Li-lu Marie
authors.initials: LL
authors.lastname: Duan
authors.forename: Li-hui
authors.initials: LH
authors.lastname: Liu
authors.forename: Zhi-dong
authors.initials: ZD
authors.lastname: Ge
authors.forename: John A
authors.initials: JA
authors.lastname: Auchampach
authors.forename: Garrett J
authors.initials: GJ
authors.lastname: Gross
authors.forename: Dayue Darrel
authors.initials: DD
authors.lastname: Duan
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D057775:Ischemic Postconditioning; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010477:Perfusion
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D053148:Caspase 3