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Remote Ischemic Preconditioning Cardio-protection via Enhanced Cell Volume Regulation Requires Activation of Swelling-Activated Chloride (Icl-Swell) Channels

Gregory J Wilson, Krista M Hawrylyshyn, Silvia Cioci, Sheena Guglani and Roberto J Diaz

Introduction

We have previously shown that remote ischemic preconditioning induced in cardiomyocytes by a brief direct incubation in rabbit blood dialysate, originated from other rabbits initially subjected to brief periods of limb ischemia/ reperfusion, given prior exposure to a prolonged ischemia/reperfusion protects cardiomyocytes against necrosis. In this study, we examined the hypothesis that sarcolemmal protein kinase C epsilon interacts with the swellingactivated Cl- channel to both enhance cardiomyocyte volume regulation and protect against cardiomyocyte necrosis in limb ischemia/reperfusion remote ischemic preconditioning.

Methods

Cultured (forty-eight hours) rabbit cardiomyocytes (control and remote ischemic preconditioned dialysate treated) were, after stabilization, subjected to either thirty-minute hypo-osmotic stress or to seventy-five minutes of simulated ischemia (severe hypoxia plus metabolic inhibition) followed by sixty minutes of simulated reperfusion (in oxygenated media), with or without a specific swelling-activated chloride channel inhibitor or its vehicle given ten minutes prior and during the hypo-osmotic stress or the simulate ischemia, to measure peak cell swelling (between eight to twelve minutes of hypo-osmotic stress), regulatory volume decrease and cell necrosis (by trypan blue staining).

Results

Specific inhibition of swell-activated chloride channels not only substantially inhibited remote ischemic preconditioned dialysate induced protection against cardiomyocyte necrosis but it also significantly impaired cardiomyocyte volume regulation. PKCε was found to co-immunoprecipitate with ClC-3, consistent with this kinase influencing swell-activated chloride channel activity.

Conclusion

These findings indicate that swelling-activated chloride channels are essential for the cardioprotection by remote ischemic preconditioning.