title: Hypoxia induces connexin 43 dysregulation by modulating matrix metalloproteinases via MAPK signaling.
abstract: Connexin 43 (Cx43) is a major structural protein found in the gap junctions of the ventricular myocardium and a major determinant of its electrical properties. The effects of matrix metalloproteinases (MMPs), the mitogen-activated protein kinase (MAPK) signaling pathway, transcription factor NF-kB, and activator protein-1 (AP-1)/c-Jun on the regulation of Cx43 gene expression in H9c2 cardiomyocytes were assessed. The MAPK signaling pathway (MEK/ERK1/2 and PI3K) and transcription factors NF-kB and AP-1/c-Jun were inhibited, then Cx43 expression was assessed using Western blot analysis, and MMP-9 activity was assessed using gelatin zymography. Hypoxia decreased the Cx43 protein level by approximately 30-50 %. Doxycycline (10 μg/mL), an inhibitor of MMP, markedly attenuated the hypoxia-induced downregulation of Cx43 protein expression at 6 h. The hypoxia-induced decrease in Cx43 protein expression was significantly reversed by U0126 (10 μM), a MEK/ERK1/2 inhibitor, at 6 and 12 h; LY294002 (30 μM), a PI3K inhibitor, downregulated Cx43 expression. Hypoxia-induced MMP-9 activation was inhibited by treatment with LY294002, U0126, and, most especially, U0126. JSH-23 (30 μM), an NF-kB inhibitor, and SP600125 (10 μM), an AP-1/c-Jun inhibitor, attenuated the loss of Cx43. These results suggest that MAPK signaling and the activities NF-kB and MMPs play an important roles in the regulation of Cx43 expression.
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Guangxi Medical University, Nanning, People's Republic of China.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Wu
authors.forename: Wen
authors.initials: W
authors.lastname: Huang
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.forename: Laval Andy
authors.initials: LA
authors.lastname: Alain
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D018031:Connexin 43 / Q000096:biosynthesis / Q000378:metabolism*; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010655:Phenylenediamines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C549066:4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine; D000873:Anthracenes; D002070:Butadienes; D002867:Chromones; D018031:Connexin 43; D004791:Enzyme Inhibitors; C580592:Gja1 protein, rat; D009025:Morpholines; D016328:NF-kappa B; D009570:Nitriles; D010655:Phenylenediamines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018808:Transcription Factor AP-1; C113580:U 0126; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D004318:Doxycycline