title: The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: INSERM U1042, Grenoble, France. claire.arnaud@ujf-grenoble.fr
authors.forename: Claire
authors.initials: C
authors.lastname: Arnaud
authors.forename: Pauline C
authors.initials: PC
authors.lastname: Beguin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lantuejoul
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pepin
authors.forename: Christiane
authors.initials: C
authors.lastname: Guillermet
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Vanessa
authors.initials: V
authors.lastname: Buatois
authors.forename: Christophe
authors.initials: C
authors.lastname: Ribuot
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Baguet
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Patrick
authors.initials: P
authors.lastname: Levy
authors.forename: Maurice
authors.initials: M
authors.lastname: Dematteis
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008853:Microscopy; D012891:Sleep Apnea Syndromes / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
chemical_list: D018946:Chemokine CCL5