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(Circulation. 2004;110:700-704.)
© 2004 American Heart Association, Inc.

Original Articles

Targeted Inactivation of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Gene Prevents Ischemic Preconditioning in Isolated Mouse Heart

Hong Chen, MD, PhD^*; Luis L. Liu, MD, MSc^*; Linda L. Ye, MD; Conor McGuckin, BS; Susan Tamowski, BS; Paul Scowen, BS; Honglin Tian, PhD; Keith Murray, BS; William J. Hatton, PhD; Dayue Duan, MD, PhD

From the Department of Pharmacology and Center of Biomedical Research Excellence, University of Nevada School of Medicine, Reno. Dr. Hong Chen is now at the Department of Pharmacology and Shanghai Institute of Hypertension, Shanghai Second Medical University, Shanghai, China.

Correspondence to Dayue Duan, MD, PhD, FAHA, Associate Professor, Center of Biomedical Research Excellence, Department of Pharmacology, University of Nevada School of Medicine, Manville Medical Building Room 9/MS 318, Reno, NV 89557-0270. E-mail dduan{at}med.unr.edu

Received November 20, 2003; de novo received February 6, 2004; revision received March 10, 2004; accepted March 17, 2004.

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.

Methods and 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.

Key Words: ischemia • myocardial infarction • hemodynamics • ion channels • genes

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