Kcne2 deletion attenuates acute post-ischaemia/reperfusion myocardial infarction.

AIMS:Most cardiac arrhythmia-associated genes encode ion channel subunits and regulatory proteins that are also expressed outside the heart, suggesting that diseases linked to their disruption may be multifactorial. KCNE2 is a ubiquitously expressed potassium channel β subunit associated with cardiac arrhythmia, atherosclerosis, and myocardial infarction (MI) in human populations. Here, we tested the hypothesis that Kcne2 disruption in mice would influence the acute outcome of experimentally induced MI. METHODS AND RESULTS:One-year-old male Kcne2⁺/⁺ and Kcne2⁻/⁻ mice were subjected to cardiac ischaemia/reperfusion injury (IRI) by left anterior descending coronary artery ligation. After reperfusion (3 h), infarct size and markers of tissue damage were quantified. Unexpectedly, post-reperfusion, Kcne2⁻/⁻ mice exhibited 40% lower infarct size, decreased myocardial apoptosis and damage, and more than two-fold lower serum levels of damage markers, lactate dehydrogenase and creatine kinase, than Kcne2⁺/⁺ mice. Kcne2 deletion, despite increasing normalized heart weight and prolonging baseline QTc by 70%, helped preserve post-infarct cardiac function (quantified by a Millar catheter), with parameters including left ventricular maximum pressure, max dP/dt (P < 0.01), contractility index, and pressure/time index (P < 0.05) all greater in Kcne2⁻/⁻ compared with Kcne2⁺/⁺ mice. Western blotting indicated two-fold-increased glycogen synthase kinase 3β (GSK-3β) phosphorylation (inactivation) before and after IRI (P < 0.05) in Kcne2⁻/⁻ mice compared with Kcne2⁺/⁺ mice. GSK-3β inhibition by SB216763 mimicked in Kcne2⁺/⁺ mice the cardioprotective effects of Kcne2 deletion, but did not further enhance them in Kcne2⁻/⁻mice, suggesting that GSK-3β inactivation was a primary cardioprotective mechanism arising from Kcne2 deletion. CONCLUSIONS:Kcne2 deletion preconditions the heart, attenuating the acute tissue damage caused by an imposed IRI. The findings contribute further evidence that genetic disruption of arrhythmia-associated ion channel genes has cardiac ramifications beyond abnormal electrical activity.

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