The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition

Autor: Arnaud, Claire, Beguin, Pauline, Lantuejoul, Sylvie, Pepin, Jean-Louis, Guillermet, Christiane, Pelli, Graziano, Burger, Fabienne, Buatois, Vanessa, Ribuot, Christophe, Baguet, Jean-Philippe, Mach, François, Levy, Patrick, Dematteis, Maurice
Přispěvatelé: Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pathologie, CHU Grenoble, Laboratoire du sommeil et EFCR, Division of Cardiology, Geneva University Hospital (HUG), Novimmune SA, Radiopharmaceutiques biocliniques, Département de cardiologie et hypertension, Pôle Pluridisciplinaire de Médecine, This study was supported by grants from AGIR@dom to M.D. and C.A., Fondation pour la Recherche Médicale (France) to C.A. and the Swiss National Science Foundation to F.M. (#3200BO-105896)., Arnaud, Claire
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Zdroj: American Journal of Respiratory and Critical Care Medicine
American Journal of Respiratory and Critical Care Medicine, 2011, 184 (6), pp.724-31. ⟨10.1164/rccm.201012-2033OC⟩
ISSN: 1073-449X
1535-4970
DOI: 10.1164/rccm.201012-2033OC⟩
Popis: International audience; RATIONALE: The highly prevalent obstructive sleep apnea syndrome (OSA) with its main component intermittent hypoxia (IH) is a risk factor for cardiovascular mortality. The poor knowledge of its pathophysiology has limited the development of specific treatments, whereas the gold standard treatment, continuous positive airway pressure, may not fully reverse the chronic consequences of OSA and has limited acceptance in some patients. OBJECTIVES: To examine the contribution of IH-induced inflammation to the cardiovascular complications of OSA. Methods: We investigated systemic and vascular inflammatory changes in C57BL6 mice exposed to IH (21-5% Fi(O(2)), 60-s cycle) or normoxia 8 hours per day up to 14 days. Vascular alterations were reassessed in mice treated with a blocking antibody of regulated upon activation, normal T-cell expressed and secreted (RANTES)/CC chemokine ligand 5 (CCL5) signaling pathway, or with the IgG isotype control throughout the IH exposure. MEASUREMENTS AND MAIN RESULTS: IH induced systemic inflammation combining increased splenic lymphocyte proliferation and chemokine expression, with early and predominant RANTES/CCL5 alterations, and enhanced splenocyte migration toward RANTES/CCL5. IH also induced structural and inflammatory vascular alterations. Leukocyte-endothelium adhesive interactions were increased, attested by leukocyte rolling and intercellular adhesion molecule-1 expression in mesenteric vessels. Aortas had increased intima-media thickness with elastic fiber alterations, mucoid depositions, nuclear factor-κB-p50 and intercellular adhesion molecule-1 overexpression, hypertrophy of smooth-muscle cells overexpressing RANTES/CCL5, and adventitial-periadventitial T-lymphocyte infiltration. RANTES/CCL5 neutralization prevented both intima-media thickening and inflammatory alterations, independently of the IH-associated proatherogenic dyslipidemia. CONCLUSIONS: Inflammation is a determinant mechanism for IH-induced preatherosclerotic remodeling involving RANTES/CCL5, a key chemokine in atherogenesis. Characterization of the inflammatory response could allow identifying at-risk patients for complications, and its pharmacologic manipulation may represent a potential complementary treatment of sleep apnea consequences.
Databáze: OpenAIRE
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