Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion

Article Article scientifique Article Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion eng 2010 author Chadjichristos Christos 135640 author Scheckenbach K E. L. author van Veen T. A. author Richani Sarieddine Maya 552207 author de Wit C. author Yang Z. author Roth I. author Bacchetta Marc 22941 author Viswambharan H. author Foglia Bernard 120721 author Dudez Tecla 26321 author van Kempen M. J. author Coenjaerts F. E. author Miquerol L. author Deutsch U. author Jongsma H. J. author Chanson Marc 0000-0001-8104-2090 32865 author Kwak Brenda 0000-0003-0015-0044 113350 123-131 10.1161/CIRCULATIONAHA.109.867176 20026782 0009-7322 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.109.867176 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. Methods and 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. 5'-Nucleotidase/metabolism Animals Atherosclerosis/immunology/pathology/physiopathology Cell Adhesion/immunology Cells, Cultured Connexins/genetics/metabolism Endothelial Cells/metabolism/pathology Gap Junctions/metabolism Green Fluorescent Proteins/genetics Mice Mice, Transgenic Monocytes/metabolism/pathology RNA, Small Interfering Signal Transduction/immunology Vasculitis/immunology/pathology/physiopathology Dewey 616.07 Dewey 618 Swiss National Science Foundation The role of connexin-mediated intercellular communication in atherosclerotic disease and its complications 116897 CH Careers Swiss National Science Foundation Endothelial dysfunction in metabolic syndrome (insulin resistance syndrome): Role of Rho/Rho-kinase pathway and protective effect of HDL/ApoA-1 105917 CH Projects Swiss National Science Foundation ROLE OF CONNEXINS IN THE INNATE IMMUNE RESPONSE OF THE NORMAL AND CYSTIC FIBROSIS LUNG 119739 CH Projects 137 Département de pathologie et immunologie 21F 58 Département de pédiatrie, gynécologie et obstétrique 223 false 397 Connexines et pathologies cardiovasculaires 665 180 Mucoviscidose et jonctions communicantes 229 Circulation 121 1 30d307c3-4394-4a73-ba3e-0899b78bf701 Article (Published version) Restricted file1.pdf 3933817 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

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