0020: Role of HIF-1 in the cardiac remodeling and inotropic effects of chronic intermittent hypoxia

Abstract

Obstructive sleep apnea (OSA) is an important risk factor for cardiovascular morbidity and mortality. Chronic intermittent hypoxia (IH), a major component of OSA, has been shown to induce cardiovascular complications (hypertension, vascular remodelling, increased infarct size). We have shown that the hypoxia sensitive transcription factor HIF-1 is involved in the cardiovascular effects of IH. The α subunit of HIF-1 is degraded in normoxia (N) following prolyl hydroxylation by prolyl hydroxylase domain containing enzymes (PHD1, PHD2 and PHD3) while it is stabilized by PHD inactivation during hypoxia. The aim of the present study was to further explore the myocardial effects of IH and HIF-1 by assessing cardiac function and remodelling in mice models overexpressing or under expressing HIF-1α. For this, the response to IH was investigated in two strains of mice partially deficient for the genes encoding for PHD2 and HIF-1α, respectively. Mice were exposed in their cages, 8 h/day during 14 days, to 1-min cycles of IH (30s of 5% FiO2 followed by 30s of room air) or N (similar cycles of room air only). After exposure, the Fulton index (RV/LV+S) was evaluated in all experimental groups and cardiac contractility was assessed in heterozygous HIF-1α null mice and their respective controls. Exposure to IH induced right ventricular hypertrophy in control animals (Fulton index: 0.298 ± 0.010 vs 0.264 ± 0.036 in N mice). This effect of IH was enhanced by partial PHD-2 deletion (0.329 ± 0.014 vs 0.270 ± 0.014 in control mice) and abolished in heterozygous HIF-1α null mice (0.284 ± 0.008 vs 0.298 ± 0.012 in control mice). We also observed a significant increase in left ventricular developed pressure and maximal dP/dt after IH exposure in WT mice. This effect was absent in mice with partial HIF-1 deficiency.In conclusion, this study confirms the role of HIF-1 in the deleterious cardiovascular adaptation to IH leading to cardiac remodelling and increased contractility.