Abstract
BackgroundPreconditioning stimuli conducted in remote organs can protect the heart against subsequent ischemic injury, but effects on arrhythmogenesis and sudden cardiac death (SCD) are unclear. Here, we investigated the effect of remote liver ischemia preconditioning (RLIPC) on ischemia/reperfusion (I/R)-induced cardiac arrhythmia and sudden cardiac death (SCD) in vivo, and determined the potential role of ERK/GSK-3βsignaling.Methods/ResultsMale Sprague Dawley rats were randomized to sham-operated, control, or RLIPC groups. RLIPC was induced by alternating four 5-minute cycles of liver ischemia with 5-minute intermittent reperfusions. To investigate I/R-induced arrhythmogenesis, hearts in each group were subsequently subjected to 5-minute left main coronary artery ligation followed by 20-minute reperfusion. RLIPC reduced post-I/R ventricular arrhythmias, and decreased the incidence of SCD >threefold. RLIPC increased phosphorylation of cardiac ERK1/2, and GSK-3β Ser9 but not Tyr216 post-I/R injury. Inhibition of either GSK-3β (with SB216763) or ERK1/2 (with U0126) abolished RLIPC-induced antiarrhythmic activity and GSK-3β Ser9 and ERK1/2 phosphorylation, leaving GSK-3β Tyr216 phosphorylation unchanged.ConclusionsRLIPC exerts a powerful antiarrhythmic effect and reduces predisposition to post-IR SCD. The underlying mechanism of RLIPC cardioprotection against I/R-induced early arrhythmogenesis may involve ERK1/2/GSK-3β Ser9-dependent pathways.
Highlights
Sudden cardiac death (SCD) is a leading cause of mortality and morbidity worldwide, accounting for the loss of an estimated 325,000 adult lives each year in the United States alone
We investigated the effect of remote liver ischemia preconditioning (RLIPC) on ischemia/reperfusion (I/R)-induced cardiac arrhythmia and sudden cardiac death (SCD) in vivo, and determined the potential role of extracellular signal-regulated kinase (ERK)/GSK-3βsignaling
The anaesthetized rats were randomized to a sham-operated group (”Sham”, hepatic arterial and venous trunk were exposed without intervention, chests were opened without coronary artery ligation), control group (CON, no further hepatic intervention) or a remote liver ischemia preconditioning group (RLIPC)
Summary
Sudden cardiac death (SCD) is a leading cause of mortality and morbidity worldwide, accounting for the loss of an estimated 325,000 adult lives each year in the United States alone. RIPC can protect target organs against subsequent sustained episodes of ischemia or I/R injury[4]. Beneficial tolerance can be achieved in the heart, with myocardial damage or infarct size minimized by inducing alternate cycles of ischemia-reperfusion preconditioning in arteries and vessels of the limbs, mesentery, intestine or kidney, as well as abdominal aorta in various animal models[6].RIPC may even protect the myocardium as effectively as direct cardiac IPC. Preconditioning stimuli conducted in remote organs can protect the heart against subsequent ischemic injury, but effects on arrhythmogenesis and sudden cardiac death (SCD) are unclear. We investigated the effect of remote liver ischemia preconditioning (RLIPC) on ischemia/reperfusion (I/R)-induced cardiac arrhythmia and sudden cardiac death (SCD) in vivo, and determined the potential role of ERK/GSK-3βsignaling
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