title: Activation of volume regulated chloride channels protects myocardium from ischemia/reperfusion damage in second-window ischemic preconditioning.
abstract: Activation of volume regulated chloride channels (VRCCs) has been shown to be cardioprotective in ischemic preconditioning (IPC) of isolated hearts but the underlying molecular mechanisms remain unclear. Recent independent studies support that ClC-3, a ClC voltage-gated chloride channel, may function as a key component of the VRCCs. Thus, ClC-3 knockout (Clcn3(-/-)) mice and their age-matched heterozygous (Clcn3(+/-)) and wild-type (Clcn3(+/+)) littermates were used to test whether activation of VRCCs contributes to cardioprotection in early and/or second-window IPC. Targeted disruption of ClC-3 gene caused a decrease in the body weight but no changes in heart/body weight ratio. Telemetry ECG and echocardiography revealed no differences in ECG and cardiac function under resting conditions among all groups. Under treadmill stress (10 m/min for 10 min), the Clcn3(-/-) mice had significant slower heart rate (648±12 bpm) than Clcn3(+/+) littermates (737±19 bpm, n=6, P<0.05). Ex vivo IPC in the isolated working-heart preparations protected cardiac function during reperfusion and significantly decreased apoptosis and infarct size in all groups. In vivo early IPC significantly reduced infarct size in all groups including Clcn3(-/-) mice (22.7±3.7% vs control 40.1±4.3%, n=22, P=0.004). Second-window IPC significantly reduced apoptosis and infarction in Clcn3(+/+) (22.9±3.2% vs 45.7±5.4%, n=22, P<0.001) and Clcn3(+/-) mice (27.5±4.1% vs 42.2±5.7%, n=15, P<0.05) but not in Clcn3(-/-) littermates (39.8±4.9% vs 41.5±8.2%, n=13, P>0.05). Impaired cell volume regulation of the Clcn3(-/-) myocytes may contribute to the failure of cardioprotection by second-window IPC. These results strongly support that activation of VRCCs may play an important cardioprotective role in second-window IPC.
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557-0318, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Bozeat
authors.forename: Sunny Yang
authors.initials: SY
authors.lastname: Xiang
authors.forename: Linda L
authors.initials: LL
authors.lastname: Ye
authors.forename: Tammy Y
authors.initials: TY
authors.lastname: Yao
authors.forename: Marie L
authors.initials: ML
authors.lastname: Duan
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Burkin
authors.forename: Fred S
authors.initials: FS
authors.lastname: Lamb
authors.forename: Dayue Darrel
authors.initials: DD
authors.lastname: Duan
mesh_terms: D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D053148:Caspase 3 / Q000378:metabolism; D048429:Cell Size; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D004562:Electrocardiography; D006339:Heart Rate; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D010805:Physical Conditioning, Animal
chemical_list: D018118:Chloride Channels; C115376:ClC-3 channel; D053148:Caspase 3