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

Chadjichristos, Christos E.; Scheckenbach, K. E. L.; Veen, T. A. B. van; Richani Sarieddine, M. Z.; Wit, C. de; Yang, Zhihong; Roth, I.; Bacchetta, M.; Viswambharan, Hema; Foglia, B.; Dudez, T.; Kempen, M. J. A. van; Coenjaerts, F. E. J.; Miquerol, L.; Deutsch, U.; Jongsma, H. J.; Chanson, M.; Kwak, B. R.

doi:10.1161/CIRCULATIONAHA.109.867176

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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

21.12.2009

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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

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