title: K ATP channel agonists preserve connexin43 protein in infarcted rats by a protein kinase C-dependent pathway.
abstract: Downward remodelling of gap junctional proteins between myocytes may trigger ventricular arrhythmia after myocardial infarction. We have demonstrated that ATP-sensitive potassium (K(ATP)) channel agonists attenuated post-infarction arrhythmias. However, the involved mechanisms remain unclear. The purpose of this study was to determine whether K(ATP) 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 PKC(ε) in the modulation of connexin43 level, carbachol and myristoylated PKC(ε) 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 K(ATP) channel agonists, assessed by immunofluorescent analysis, Western blotting, and real-time quantitative reverse transcription-PCR of connexin43. Arrhythmic scores during programmed stimulation in the K(ATP) channel agonists-treated rats were significantly lower than those treated with vehicle. The beneficial effects of K(ATP) channel agonists were blocked by either glibenclamide or 5-hydroxydecanoate. Addition of the PKC activator, phorbol 12-myristate 13-acetate and the specific PKC(ε) agonist, carbachol, blocked the effects of nicorandil on connexin43 phosphorylation and dye permeability. The specific PKC(ε) antagonist, myristoylated PKC(ε) V1-2 peptide, did not have additional beneficial effects on connexin43 phosphorylation compared with rats treated with nicorandil alone. Chronic use of K(ATP) channel agonists after infarction, resulting in enhanced connexin43 level through a PKC(ε)-dependent pathway, may attenuate the arrhythmogenic response to programmed electrical stimulation.
authors.affiliation: Department of Medicine, Cardiology Section, Taipei Medical University and Chi-Mei Medical Center, Tainan, Taiwan. tsungm.lee@msa.hinet.net
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
authors.forename: Chih-Chan
authors.initials: CC
authors.lastname: Lin
authors.forename: Hsiao-Yin
authors.initials: HY
authors.lastname: Lien
authors.forename: Chien-Chang
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D018031:Connexin 43 / Q000378:metabolism*; D017931:DNA Primers; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018031:Connexin 43; D017931:DNA Primers; D000255:Adenosine Triphosphate; D011493:Protein Kinase C