Abstract 1425: VSOACs Play an Important Cardioprotective Role in Late Ischemic Preconditioning in Mouse Heart
Background: Activation of volume-sensitive osmolyte and anion channels (VSOACs) has been shown to be involved in ischemic preconditioning (IPC) protection of isolated rabbit heart but the underlying molecular mechanisms remain unclear. Recent accumulative evidence strongly supports that ClC-3 may encode the VSOACs in the heart. Thus, ClC-3 knockout (KO) mice were used to directly test the hypothesis that activation of VSOACs may contribute to cardioprotection in both early and late IPC.
Methods: Multiple approaches including telemetry ECG and echocardiography were used to assess the cardiovascular phenotype under normal, stressed (treadmill or ischemia), and in vivo early and late IPC conditions in age matched ClC-3 wild type (WT), heterozygous (HT) and KO littermates.
Targeted disruption of ClC-3 gene caused a decrease in the body weight (21.2±1.3 vs WT 28.3±1.2 g, n=68, P<0.05) but no significant changes in heart weight/body weight ratio (5.3±0.2 vs WT 5.2±0.2), cardiac function or ECG as estimated by M-mode echocardiogram and telemetry ECG analysis under rest conditions. Under treadmill stress (10 m/min for 10 min), the heart rate was markedly slower in KO (648±12 bpm) than in WT (737±19 bpm, n=6, P<0.05) and the QRS (15±1 ms) and Q-T (30±1 ms) intervals in KO mice were significantly longer than in WT (13±1 and 26±2 ms, respectively, n=6, P<0.05).
Early IPC significantly reduced infarct size caused by 30 min ischemia in all groups including ClC-3 KO mice (control 40.1±4.3% vs. IPC 22.7±3.7%, n=22, P<0.05).
Late IPC significantly reduced infarction in WT (22.9 ± 3.2% vs control 45.7±5.4%, n=22, P<0.05) and HT mice (28.4±8.1% vs control 42.9 ± 9.7%, n=17, P=<0.05) but not in ClC-3 KO littermates (39.8 ± 4.9% vs control 41.5 ± 8.2%, n=13, P=NS).
Conclusions: These results indicate that VSOACs may play an important cardioprotective role in the late IPC but not in the early IPC.