title: Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice.
abstract: BACKGROUND
  Gap junctions allow the direct exchange of ions and small molecules between cells in contact, thus coordinating physiological processes such as cell growth and differentiation. We have recently demonstrated increased expression of the gap junction protein connexin43 (Cx43) in specific subsets of cells in atherosclerotic lesions. Because the development of atherosclerosis depends critically on paracrine cell-to-cell interactions, we hypothesized that direct intercellular communication via gap junctions may be another factor controlling atherogenesis.
  
  
  RESULTS
  The role of Cx43 in atherogenesis was examined by use of both a genetic and a pharmacological approach. First, atherosclerosis-susceptible LDL receptor-deficient (LDLR-/-) mice with normal (Cx43+/+) or reduced (Cx43+/-) levels of Cx43 were fed a cholesterol-rich diet for 14 weeks. The progression of atherosclerosis was reduced by 50% (P<0.01) in the thoracoabdominal aorta and in the aortic roots of Cx43+/-LDLR-/- mice compared with Cx43+/+LDLR-/- controls. Atheroma in Cx43+/-LDLR-/- mice contained fewer inflammatory cells and exhibited thicker fibrous caps with more collagen and smooth muscle cells. Next, we observed that HMG-CoA reductase inhibitors, or "statins," lipid-lowering drugs well known for their pleiotropic antiatherogenic effects, reduced Cx43 expression in primary human vascular cells in vitro. Atheroma of LDLR-/- mice treated orally with pravastatin contained fewer inflammatory cells and exhibited thicker fibrous caps than controls. This was associated with reduced Cx43 expression in lesions of statin-treated mice.
  
  
  CONCLUSIONS
  These data indicate a critical role for Cx43-mediated gap junctional communication in atherosclerotic plaque formation.
authors.affiliation: Division of Cardiology, University Hospital, Geneva, Switzerland.
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Kwak
authors.forename: Niels
authors.initials: N
authors.lastname: Veillard
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Flore
authors.initials: F
authors.lastname: Mulhaupt
authors.forename: Richard W
authors.initials: RW
authors.lastname: James
authors.forename: Marc
authors.initials: M
authors.lastname: Chanson
authors.forename: François
authors.initials: F
authors.lastname: Mach
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D018031:Connexin 43; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL