Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion
| Autor: | F.E.J. Coenjaerts, Brenda R. Kwak, Marc Chanson, Marc Bacchetta, Lucile Miquerol, Isabelle Roth, Zhihong Yang, T. A. B. van Veen, Urban Deutsch, Christos Chadjichristos, Habo J. Jongsma, M.J.A. van Kempen, M. Z. Richani Sarieddine, Tecla Dudez, K.E.L. Scheckenbach, Hema Viswambharan, Bernard Foglia, C. de Wit |
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| Přispěvatelé: | Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), laboratory of clinical investigation III [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Department of Internal Medicine Specialties [Geneva, Switzerland], Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Pathology
Cell Adhesion/immunology Connexins/*genetics/metabolism Vasculitis/immunology/pathology/*physiopathology 030204 cardiovascular system & hematology Connexins Monocytes Green Fluorescent Proteins/genetics Transgenic Mice 0302 clinical medicine RNA Small Interfering Endothelial dysfunction 5'-Nucleotidase ComputingMilieux_MISCELLANEOUS Cells Cultured 0303 health sciences ddc:618 Cultured Gap Junctions 3. Good health medicine.anatomical_structure 5'-Nucleotidase/*metabolism medicine.symptom Cardiology and Cardiovascular Medicine Gap Junctions/metabolism Signal Transduction Vasculitis medicine.medical_specialty Atherosclerosis/immunology/pathology/*physiopathology Endothelium Transgene Cells Green Fluorescent Proteins Mice Transgenic Inflammation [SDV.BC]Life Sciences [q-bio]/Cellular Biology Small Interfering Proinflammatory cytokine 03 medical and health sciences Physiology (medical) Internal medicine Cell Adhesion medicine Animals Cell adhesion 030304 developmental biology Signal Transduction/immunology business.industry Vascular disease Endothelial Cells/metabolism/*pathology Monocyte Endothelial Cells Monocytes/metabolism/pathology Atherosclerosis medicine.disease Endocrinology RNA business [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Circulation Circulation, 2010, 121 (1), pp.123-131. ⟨10.1161/CIRCULATIONAHA.109.867176⟩ Circulation, American Heart Association, 2010, 121 (1), pp.123-131 Circulation, Vol. 121, No 1 (2010) pp. 123-131 |
| ISSN: | 0009-7322 1524-4539 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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