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Endothelial-specific deletion of Connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion

  • Chadjichristos, Christos E. Division of Cardiology Geneva University Hospitals Switzerland
  • Scheckenbach, K. E. L. Department of Pediatrics Geneva University Hospitals Switzerland
  • Veen, T. A. B. van Department of Medical Physiology, University Medical Center Utrecht, the Netherlands
  • Richani Sarieddine, M. Z. Department of Pediatrics Geneva University Hospitals Switzerland - Department of Medical Physiology, University Medical Center Utrecht, the Netherlands
  • Wit, C. de Institut für Physiologie, Universität zu Lübeck, Lübeck, German
  • Yang, Zhihong Division of Physiology, University of Fribourg, Switzerland
  • Roth, I. Division of Cardiology Geneva University Hospitals Switzerland
  • Bacchetta, M. Department of Pediatrics Geneva University Hospitals Switzerland
  • Viswambharan, Hema Division of Physiology, University of Fribourg, Switzerland
  • Foglia, B. Department of Pediatrics Geneva University Hospitals Switzerland - Division of Cardiology Geneva University Hospitals Switzerland
  • Dudez, T. Department of Pediatrics Geneva University Hospitals Switzerland
  • Kempen, M. J. A. van Department of Medical Physiology, University Medical Center Utrecht, the Netherlands
  • Coenjaerts, F. E. J. Department of Medical Physiology, University Medical Center Utrecht, the Netherlands
  • Miquerol, L. Developmental Biology Institute of Marseille-Luminy, France
  • Deutsch, U. Theodor Kocher Institute, University of Bern, Switzerland
  • Jongsma, H. J. Department of Medical Physiology, University Medical Center Utrecht, the Netherlands
  • Chanson, M. Department of Pediatrics Geneva University Hospitals Switzerland
  • Kwak, B. R. Division of Cardiology Geneva University Hospitals Switzerland
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    21.12.2009
Published in:
  • Circulation. - 2010, vol. 121, p. 123-131
English 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.
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/301279
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