Targeting connexin 43 prevents platelet-derived growth factor-BB-induced phenotypic change in porcine coronary artery smooth muscle cells

Article Article scientifique Article Targeting connexin 43 prevents platelet-derived growth factor-BB-induced phenotypic change in porcine coronary artery smooth muscle cells eng 2008 author Chadjichristos Christos E. author Morel Sandrine 0000-0003-1538-3553 654076 author Derouette Jean-Paul 88087 author Sutter Dominique 135621 author Roth Daniel 57438 author Brisset Anne C. author Bochaton-Piallat Marie-Luce 0000-0001-8408-8932 23951 Marie-Luce Piallat author Kwak Brenda 0000-0003-0015-0044 113350 653-660 10.1161/CIRCRESAHA.107.170472 18239136 0009-7330 http://circres.ahajournals.org/cgi/content/full/102/6/653 We previously reported that reducing the expression of the gap junction protein connexin (Cx)43 in mice restricts intimal thickening formation after acute vascular injury by limiting the inflammatory response and the proliferation and migration of smooth muscle cells (SMCs) toward the damaged site. SMC populations isolated from porcine coronary artery exhibit distinct phenotypes: spindle-shaped (S) and rhomboid (R). S-SMCs are predominant in the normal media, whereas R-SMCs are recovered in higher proportion from stent-induced intimal thickening, suggesting that they participate in the restenotic process. Here, we further investigate the relationship between connexin expression and SMC phenotypes using porcine coronary artery SMCs. Cx40 was highly expressed in normal media of porcine coronary artery in vivo, whereas Cx43 was barely detectable. In contrast, Cx40 was downregulated and Cx43 was markedly upregulated in stent-induced intimal thickening. In vitro, S-SMCs expressed Cx40 and Cx43. In R-SMCs, Cx43 expression was increased and Cx40 was absent. We confirmed that S-SMCs treated with platelet-derived growth factor-BB acquire an R phenotype. This was accompanied by an upregulation of Cx43 and a loss of Cx40. Importantly, platelet-derived growth factor-BB-induced S-to-R phenotypic change was prevented by a reduction of Cx43 expression with antisense, ie, S-SMCs retained their typical elongated appearance and the expression of alpha-smooth muscle actin, a well-known SMC differentiation marker, whereas the expression of S100A4, a typical marker of R-SMCs, was prevented. In conclusion, limiting Cx43 expression in S-SMCs prevents platelet-derived growth factor-BB-induced S-to-R modulation. This suggests that Cx43 may be an additional target for local delivery strategies aimed at reducing restenosis. Actins/metabolism Animals Cell Differentiation Cell Movement Cell Shape Cells Cultured Connexin 43/antagonists & inhibitors/genetics/metabolism Connexins/metabolism Coronary Stenosis/etiology/metabolism/pathology Coronary Vessels/metabolism/pathology Disease Models Animal Female Gap Junctions/drug effects/metabolism Glycyrrhetinic Acid/analogs & derivatives/pharmacology Muscle Smooth Vascular/drug effects/metabolism/pathology Myocytes Smooth Muscle/drug effects/metabolism/pathology Peptides/pharmacology Phenotype Platelet-Derived Growth Factor/metabolism RNA Interference RNA Small Interfering/metabolism Recombinant Proteins/metabolism S100 Proteins/metabolism Signal Transduction/drug effects Stents/adverse effects Sus scrofa Time Factors Tunica Intima/metabolism/pathology Dewey 616 Dewey 616.07 137 Département de pathologie et immunologie 21F 56 Département de médecine 221 false 380 Bochaton-Piallat Marie-Luce (pathologie et immunologie) 646 397 Connexines et pathologies cardiovasculaires 665 Circulation research 102 6 f7d4a19b-b5fd-4205-8ab1-f9eac55b4b52 Article (Accepted version) Restricted 18239136.pdf 726666 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de médecine

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Targeting connexin 43 prevents platelet-derived growth factor-BB-induced phenotypic change in porcine coronary artery smooth muscle cells	Circulation research	2008	668	6

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