title: Reduced connexin43 expression limits neointima formation after balloon distension injury in hypercholesterolemic mice.
abstract: BACKGROUND
  Reducing the expression of the gap junction protein connexin43 (Cx43) inhibits the progression of atherosclerosis, a chronic inflammatory disease. Furthermore, acute vascular injury induced by percutaneous coronary interventions is associated with increased Cx43 expression in neointimal smooth muscle cells (SMCs). However, the relevance of Cx43 after acute vascular injury remains unclear.
  
  
  RESULTS
  To investigate whether reducing Cx43 expression would affect neointima formation in vivo, we subjected hypercholesterolemic Cx43+/- LDL receptor-deficient (LDLR-/-) mice and Cx43+/+LDLR-/- control littermates to carotid balloon distension injury, which induced marked endothelial denudation and activation of medial SMCs. We observed decreased macrophage infiltration in Cx43+/-LDLR-/- mice 7 days after injury. Similarly, peritoneal macrophages isolated from Cx43+/-LDLR-/- mice showed reduced migration in vitro compared with Cx43+/+LDLR-/- macrophages. Interestingly, Cx43+/-LDLR-/- macrophages also displayed decreased chemotactic activity for SMCs. In addition, we observed less SMC infiltration and proliferation in Cx43+/-LDLR-/- mice 7 and 14 days after balloon angioplasty. Likewise, Cx43+/-LDLR-/- SMCs showed decreased proliferation and migration in vitro compared with Cx43+/+LDLR-/- cells. All these events resulted in a reduction of neointimal thickening after vascular injury in Cx43+/-LDLR-/- mice.
  
  
  CONCLUSIONS
  The present study shows for the first time that reducing Cx43 limits neointima formation after acute vascular injury by decreasing the inflammatory response and reducing SMC migration and proliferation. Thus, decreasing Cx43 expression may offer a novel therapeutic strategy for reducing restenosis after percutaneous coronary intervention.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Geneva University Hospitals, 64 Avenue de la Roseraie, CH-1211 Geneva, Switzerland.
authors.forename: Christos E
authors.initials: CE
authors.lastname: Chadjichristos
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.forename: Isabelle
authors.initials: I
authors.lastname: Roth
authors.forename: Esther
authors.initials: E
authors.lastname: Sutter
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Marc
authors.initials: M
authors.lastname: Chanson
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Kwak
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D002340:Carotid Artery Diseases / Q000209:etiology / Q000628:therapy*; D016893:Carotid Stenosis / Q000209:etiology / Q000517:prevention & control*; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured / Q000378:metabolism; D002630:Chemotactic Factors / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D018031:Connexin 43 / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000473:pathology; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications* / Q000235:genetics; D006965:Hyperplasia; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012008:Recurrence; D014280:Triglycerides / Q000097:blood; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D002630:Chemotactic Factors; D018031:Connexin 43; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol