title: Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion.
abstract: BACKGROUND
  Endothelial dysfunction is the initiating event of atherosclerosis. The expression of connexin40 (Cx40), an endothelial gap junction protein, is decreased during atherogenesis. In the present report, we sought to determine whether Cx40 contributes to the development of the disease.
  
  
  RESULTS
  Mice with ubiquitous deletion of Cx40 are hypertensive, a risk factor for atherosclerosis. Consequently, we generated atherosclerosis-susceptible mice with endothelial-specific deletion of Cx40 (Cx40del mice). Cx40del mice were indeed not hypertensive. The progression of atherosclerosis was increased in Cx40del mice after 5 and 10 weeks of a high-cholesterol diet, and spontaneous lesions were observed in the aortic sinuses of young mice without such a diet. These lesions showed monocyte infiltration into the intima, increased expression of vascular cell adhesion molecule-1, and decreased expression of the ecto-enzyme CD73 in the endothelium. The proinflammatory phenotype of Cx40del mice was confirmed in another model of induced leukocyte recruitment from the lung microcirculation. Endothelial CD73 is known to induce antiadhesion signaling via the production of adenosine. We found that reducing Cx40 expression in vitro with small interfering RNA or antisense decreased CD73 expression and activity and increased leukocyte adhesion to mouse endothelial cells. These effects were reversed by an adenosine receptor agonist.
  
  
  CONCLUSIONS
  Cx40-mediated gap junctional communication contributes to a quiescent nonactivated endothelium by propagating adenosine-evoked antiinflammatory signals between endothelial cells. Alteration in this mechanism by targeting Cx40 promotes leukocyte adhesion to the endothelium, thus accelerating atherosclerosis.
authors.affiliation: Division of Cardiology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: C E
authors.initials: CE
authors.lastname: Chadjichristos
authors.forename: K E L
authors.initials: KE
authors.lastname: Scheckenbach
authors.forename: T A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: M Z
authors.initials: MZ
authors.lastname: Richani Sarieddine
authors.forename: C
authors.initials: C
authors.lastname: de Wit
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: I
authors.initials: I
authors.lastname: Roth
authors.forename: M
authors.initials: M
authors.lastname: Bacchetta
authors.forename: H
authors.initials: H
authors.lastname: Viswambharan
authors.forename: B
authors.initials: B
authors.lastname: Foglia
authors.forename: T
authors.initials: T
authors.lastname: Dudez
authors.forename: M J A
authors.initials: MJ
authors.lastname: van Kempen
authors.forename: F E J
authors.initials: FE
authors.lastname: Coenjaerts
authors.forename: L
authors.initials: L
authors.lastname: Miquerol
authors.forename: U
authors.initials: U
authors.lastname: Deutsch
authors.forename: H J
authors.initials: HJ
authors.lastname: Jongsma
authors.forename: M
authors.initials: M
authors.lastname: Chanson
authors.forename: B R
authors.initials: BR
authors.lastname: Kwak
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D017629:Gap Junctions / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D014657:Vasculitis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D015720:5'-Nucleotidase; D017630:Connexins; D049452:Green Fluorescent Proteins; D034741:RNA, Small Interfering; D000097003:Gap Junction alpha-5 Protein