title: Targeting connexin 43 prevents platelet-derived growth factor-BB-induced phenotypic change in porcine coronary artery smooth muscle cells.
abstract: 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.
authors.affiliation: Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, University of Geneva, Switzerland.
authors.forename: Christos E
authors.initials: CE
authors.lastname: Chadjichristos
authors.forename: Sandrine
authors.initials: S
authors.lastname: Morel
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Derouette
authors.forename: Esther
authors.initials: E
authors.lastname: Sutter
authors.forename: Isabelle
authors.initials: I
authors.lastname: Roth
authors.forename: Anne C
authors.initials: AC
authors.lastname: Brisset
authors.forename: Marie-Luce
authors.initials: ML
authors.lastname: Bochaton-Piallat
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Kwak
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D002454:Cell Differentiation; D002465:Cell Movement; D048430:Cell Shape; D002478:Cells, Cultured; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000378:metabolism; D023921:Coronary Stenosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015607:Stents / Q000009:adverse effects; D034421:Sus scrofa; D013997:Time Factors; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D000097003:Gap Junction alpha-5 Protein
chemical_list: D000199:Actins; D000077214:Becaplermin; D018031:Connexin 43; D017630:Connexins; D006034:Glycyrrhetinic Acid; D010455:Peptides; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D009418:S100 Proteins; D000097003:Gap Junction alpha-5 Protein; C119129:18alpha-glycyrrhetinic acid