Abstract 427: Chronic Intermittent Hypoxia Induces Endothelial Insulin Resistance in vivo and in vitro

Abstract

Introduction: Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is an independent risk factor for cardiovascular disease and type 2 diabetes and is correlated with insulin resistance. Insulin stimulates production of nitric oxide (NO) in vascular endothelial cells through the IRS-1/PI3K/Akt/eNOS pathway (IRS-1, insulin receptor substrate 1; PI3K, phosphatidylinositol 3-kinase; eNOS, endothelial NO synthase). Endothelial cells directly expose to blood flow and respond to oxygen concentration change in flow. We wondered if and how CIH would affect insulin signalling/action in endothelial cells. Methods and Results: C57BL/6J mice were exposed to CIH (21%-5%, 90 s/cycle, 10 h/day) or intermittent air for 7 weeks. HUVECs were exposed to CIH (21%-5%, 1 h/cycle) for 24 h or 48 h with or without insulin. We observed that CIH increased systolic blood pressure and impaired endothelium-dependent relaxation of aortas in C57BL/6J mice. CIH increased IRS-1 phosphorylation at Ser307 and Ser612 and impaired insulin-stimulated phosphorylation of IRS-1 at Tyr896 and Akt/eNOS pathway in aortas. Furthermore, CIH activated hypoxia-inducible factor 1α (HIF-1α) and nuclear factor kappa B (NF-κB) in aortas. In vitro, CIH activated endothelial HIF-1α signaling, impaired endothelial insulin signaling and reduced insulin-mediated NO production. In addition, CIH resulted in mitochondria proton leak and elevated oxygen consumption in HUVECs. Increased oxygen consumption further leaded to endothelial hypoxia and HIF-1α induction. Pharmacological inhibition of proton leak ameliorated CIH-induced endothelial insulin resistance in HUVECs. Conclusion: Our data suggest that CIH induces insulin resistant endothelial dysfunction, which may be associated with HIF-1α induction and proton leak.