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Bosentan and HIF-1a deficiency prevent intermittent hypoxia-induced aortic inflammation and remodeling in mice.
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Demonstrates that endothelin-1 mediates hypoxia-induced vascular remodeling in mice through HIF-1 activation, highlighting a therapeutic target for sleep apnea.
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.
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Gras et al. (2015) studied Intermittent hypoxia-induced vascular inflammatory remodeling (obstructive sleep apnea model). Intermittent hypoxia and bosentan (dual endothelin receptor antagonist) vs. Normoxia and untreated wild-type controls was evaluated on Splenocyte proliferative and secretory capacities, aortic NF-kB and HIF-1 activities, aortic cytokine expression, and intima-media thickness (IMT). Bosentan treatment and HIF-1a deficiency prevented 2-week intermittent hypoxia-induced increases in aortic NF-kB activity, cytokine expression, and intima-media thickness in mice.
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