title: Endothelin-1 mediates intermittent hypoxia-induced inflammatory vascular remodeling through HIF-1 activation.
abstract: Obstructive sleep apnea (OSA) is a major risk factor for cardiovascular mortality, and apnea-induced intermittent hypoxia (IH) is known to promote various cardiovascular alterations such as vascular remodeling. However, the mechanisms that underlie IH remain incompletely investigated. We previously demonstrated that the hypoxia-inducible factor-1 (HIF-1) and endothelin-1 (ET-1) are involved in arterial hypertension and myocardial susceptibility to infarction induced by IH. Thus the objective of the present study was to investigate whether both ET-1 and HIF-1 were also involved in the vascular inflammatory remodeling induced by IH. Mice partially deficient for the Hif1α gene (HIF-1α(+/-)) and their wild-type equivalents, as well as C57BL/6J mice, treated or not with bosentan, a dual endothelin receptor antagonist, were exposed to IH or normoxia for 2 wk, 8 h/day. Splenocyte proliferative and secretory capacities, aortic nuclear factor-κB (NF-κB) and HIF-1 activities, and expression of cytokines and intima-media thickness (IMT) were measured. IH induced a systemic and aortic inflammation characterized by an increase in splenocyte proliferative and secretory capacities, aortic NF-κB activity, and cytokine expression in the aortic wall. This was accompanied by an increase in IMT. These modifications were prevented in HIF-1α(+/-) and bosentan-treated mice. The results of this study suggest that ET-1 is a major contributor to the vascular inflammatory remodeling induced by OSA-related IH, probably through HIF-1-dependent activation of NF-κB.
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble, France; INSERM, U1042, Grenoble, France; and.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Gras
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble, France; INSERM, U1042, Grenoble, France; and.
authors.forename: Elise
authors.initials: E
authors.lastname: Belaidi
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble, France; INSERM, U1042, Grenoble, France; and.
authors.forename: Anne
authors.initials: A
authors.lastname: Briançon-Marjollet
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble, France; INSERM, U1042, Grenoble, France; and CHU de Grenoble, Grenoble, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pépin
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble, France; INSERM, U1042, Grenoble, France; and.
authors.forename: Claire
authors.identifier: http://orcid.org/0000-0003-0964-9423
authors.initials: C
authors.lastname: Arnaud
authors.affiliation: Université Grenoble Alpes, Laboratoire HP2, Grenoble, France; INSERM, U1042, Grenoble, France; and diane.ribuot@univ-grenoble-alpes.fr.
authors.forename: Diane
authors.identifier: http://orcid.org/0000-0001-7589-932X
authors.initials: D
authors.lastname: Godin-Ribuot
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D059168:Carotid Intima-Media Thickness; D016207:Cytokines / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D020181:Sleep Apnea, Obstructive / Q000378:metabolism / Q000503:physiopathology; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: D016207:Cytokines; D019332:Endothelin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B
keywords: endothelin-1; hypoxia inducible factor-1; inflammation; intermittent hypoxia; nuclear factor-κB; vascular remodeling