Targeted inactivation of cystic fibrosis transmembrane conductance regulator chloride channel gene prevents ischemic preconditioning in isolated mouse heart.
BACKGROUND
Recent evidence suggests that chloride channels may be involved in ischemic preconditioning (IPC). In this study, we tested whether the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels, which are expressed in the heart and activated by protein kinase A and protein kinase C, are important for IPC in isolated heart preparations from wild-type (WT) and CFTR knockout (CFTR-/-) mice.


RESULTS
Hearts were isolated from age-matched WT or CFTR-/- (B6.129P2-Cftr(tm1Unc) and STOCKCftr(tm1Unc)-TgN 1Jaw) mice and perfused in the Langendorff or working-heart mode. All hearts were allowed to stabilize for 10 minutes before they were subjected to 30 or 45 minutes of global ischemia followed by 40 minutes of reperfusion (control group) or 3 cycles of 5 minutes of ischemia and reperfusion (IPC group) before 30 or 45 minutes of global ischemia and 40 minutes of reperfusion. Hemodynamic indices were recorded to evaluate cardiac functions. Release of creatine phosphate kinase (CPK) in the samples of coronary effluent and infarct size of the ventricles were used to estimate myocardial tissue injury. In WT adult hearts, IPC protected cardiac function during reperfusion and significantly decreased ischemia-induced CPK release and infarct size. A selective CFTR channel blocker, gemfibrozil, abrogated the protective effect of IPC. Furthermore, targeted inactivation of the CFTR gene in 2 different strains of CFTR-/- mice also prevented IPC's protection of cardiac function and myocardial injury against sustained ischemia.


CONCLUSIONS
CFTR Cl- channels may serve as novel and crucial mediators in mouse heart IPC.
Department of Pharmacology, Center of Biomedical Research Excellence, University of Nevada School of Medicine, Reno, NV 89557-0270, USA.
Hong
H
Chen
Luis L
LL
Liu
Linda L
LL
Ye
Conor
C
McGuckin
Susan
S
Tamowski
Paul
P
Scowen
Honglin
H
Tian
Keith
K
Murray
William J
WJ
Hatton
Dayue
D
Duan
D000818:Animals; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015248:Gemfibrozil / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D019194:Ischemic Preconditioning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000150:complications / Q000235:genetics / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000517:prevention & control*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D013045:Species Specificity; D016277:Ventricular Function, Left
D002712:Chlorides; D009842:Oligopeptides; C073248:Peptamen; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D015248:Gemfibrozil