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(Circulation. 2006;113:2835-2843.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Reduced Connexin43 Expression Limits Neointima Formation After Balloon Distension Injury in Hypercholesterolemic Mice

Christos E. Chadjichristos, PhD^*; Christian M. Matter, MD^*; Isabelle Roth; Esther Sutter; Graziano Pelli; Thomas F. Lüscher, MD; Marc Chanson, PhD; Brenda R. Kwak, PhD

From the Division of Cardiology, Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland (C.E.C., I.R., E.S., G.P., B.R.K.); Cardiovascular Research, Institute of Physiology, University of Zürich and Cardiovascular Center, University Hospital, Zürich, Switzerland (C.M.M., T.F.L.); Center for Integrative Human Physiology, University of Zurich, Switzerland (C.M.M.); and Laboratory of Clinical Investigation III, Department of Pediatrics, University Hospital, Geneva, Switzerland (M.C.).

Correspondence to Brenda R. Kwak, PhD, Foundation for Medical Research, Division of Cardiology, Geneva University Hospitals, 64 Avenue de la Roseraie, CH-1211 Geneva, Switzerland. E-mail Brenda.KwakChanson{at}medecine.unige.ch

Received December 12, 2005; de novo received March 21, 2006; accepted April 7, 2006.

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.

Methods and 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.

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