KATP channel agonists preserve connexin43 protein in infarcted rats by a protein kinase C-dependent pathway

摘要

Downward remodelling of gap junctional proteins between myocytes may trigger ventricular arrhythmia after myocardial infarction. We have demonstrated that ATP-sensitive potassium (KATP) channel agonists attenuated post-infarction arrhythmias. However, the involved mechanisms remain unclear. The purpose of this study was to determine whether KATP channel agonists can attenuate arrhythmias through preserving protein kinase C (PKC)-ε-dependent connexin43 level after myocardial infarction. Male Wistar rats after ligating coronary artery were randomized to either vehicle, nicorandil, pinacidil, glibenclamide or a combination of nicorandil and glibenclamide or pinacidil and glibenclamide for 4 weeks. To elucidate the role of PKCε in the modulation of connexin43 level, carbachol and myristoylated PKCε V1-2 peptide were also assessed. Myocardial connexin43 level was significantly decreased in vehicle-treated infarcted rats compared with sham. Attenuated connexin43 level was blunted after administering KATP channel agonists, assessed by immunofluorescent analysis, Western blotting, and real-time quantitative reverse transcription-PCR of connexin43. Arrhythmic scores during programmed stimulation in the KATP channel agonists-treated rats were significantly lower than those treated with vehicle. The beneficial effects of KATP channel agonists were blocked by either glibenclamide or 5-hydroxydecanoate. Addition of the PKC activator, phorbol 12-myristate 13-acetate and the specific PKCε agonist, carbachol, blocked the effects of nicorandil on connexin43 phosphorylation and dye permeability. The specific PKCε antagonist, myristoylated PKCε V1-2 peptide, did not have additional beneficial effects on connexin43 phosphorylation compared with rats treated with nicorandil alone. Chronic use of KATP channel agonists after infarction, resulting in enhanced connexin43 level through a PKCε-dependent pathway, may attenuate the arrhythmogenic response to programmed electrical stimulation.