Involvement of the HIF-1 transcription factor and of endothelin-1 in systemic inflammation and vascular remodelling induced by chronic intermittent hypoxia

 Emmanuelle GRASa, Dr. Claire ARNAUDa, Dr. Anne BRIANÇON-MARJOLLETa, Pr. Patrick LÉVYa, Pr. Diane GODIN-RIBUOTa

a Laboratoire HP2 - Inserm 1042

Background: Obstructive sleep apnea (OSA) is a public health problem, affecting at least 5% of the general population and characterized by repetitive upper airway collapse during sleep leading to intermittent hypoxia (IH). Both OSA and IH lead to various cardiovascular complications such as hypertension, vascular remodelling and atherosclerosis and are associated with oxidative-stress and systemic inflammation. The aim of this study was to investigate the role of the hypoxia sensitive transcription factor-1 (HIF-1) and one of its target genes, endothelin (ET-1), in the development of the IH-induced systemic inflammation and vascular remodelling.

Methods and results: For this, the response to IH was studied in heterozygous mice partially deficient for the a subunit of HIF-1 (Hifa +/-) and in C57BL/6 mice treated with bosentan (a non-selective endothelin receptor antagonist) throughout the period of IH exposure. All animals were exposed for 2 weeks, 8 hours per day, to 1-minute cycles of IH (30 seconds at 5% FiO2 followed by 30 seconds at room air) or to normoxia (similar cycles with room air only). Aortic intima-media thickness and systemic inflammation, assessed through splenocyte activation, were measured in the various experimental groups.

After 2 weeks of IH exposure, splenocyte activation was shown by increased proliferation in response to concanavalin A and migration in response to MCP-1, in hypoxic compared to normoxic mice. Aortic intima-media thickness was also significantly increased by IH. Treatment with bosentan or partial deletion of HIF-1a, suppressed the inflammatory response and the increase in aortic vascular wall.

Conclusion, both HIF-1 and ET-1 appear to be involved in the IH-induced systemic inflammation and vascular remodelling.

Keywords : Intermittent hypoxia; inflammation; vascular remodeling