Hypoxia‐inducible factor 1 mediates increased expression of NADPH oxidase‐2 in response to intermittent hypoxia

Abstract

Sleep-disordered breathing with recurrent apnea is associated with intermittent hypoxia (IH). Cardiovascular morbidities caused by IH are triggered by increased generation of reactive oxygen species (ROS) by pro-oxidant enzymes, especially NADPH oxidase-2 (Nox2). Previous studies showed that (i) IH activates hypoxia-inducible factor 1 (HIF-1) in a ROS-dependent manner and (ii) HIF-1 is required for IH-induced ROS generation, indicating the existence of a feed-forward mechanism. In the present study, using multiple pharmacological and genetic approaches, we investigated whether IH-induced expression of Nox2 is mediated by HIF-1 in the central and peripheral nervous system of mice as well as in cultured cells. IH increased Nox2 mRNA, protein, and enzyme activity in PC12 pheochromocytoma cells as well as in wild-type mouse embryonic fibroblasts (MEFs). This effect was abolished or attenuated by blocking HIF-1 activity through RNA interference or pharmacologic inhibition (digoxin or YC-1) or by genetic knockout of HIF-1α in MEFs. Increasing HIF-1α expression by treating PC 12 cells with the iron chelator deferoxamine for 20 h or by transfecting them with HIF-1alpha expression vector increased Nox2 expression and enzyme activity. Exposure of wild-type mice to IH (8 h/day for 10 days) up-regulated Nox2 mRNA expression in brain cortex, brain stem, and carotid body but not in cerebellum. IH did not induce Nox2 expression in cortex, brainstem, carotid body, or cerebellum of Hif1a+/− mice, which do not manifest increased ROS or cardiovascular morbidities in response to IH. These results establish a pathogenic mechanism linking HIF-1, ROS generation, and cardiovascular pathology in response to IH.

Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis

“…1073/pnas.1305961110/-/DCSupplemental. a pro-oxidant enzyme (17), whereas HIF-2 regulates superoxide dismutase 2 (Sod2), an antioxidant enzyme (11,18), which suggests that balance between HIF-α isoforms might be important for maintaining cellular redox homeostasis. Based on these studies, we tested the hypothesis that functional antagonism between HIF-1α and HIF-2α plays a critical role in O 2 sensing by regulating redox state in the CB and AM, which in turn is critical for regulation of cardio-respiratory homeostasis.…”

Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Through Low-Density Lipoprotein Receptor–Related Protein 1–Mediated Pyk2 Phosphorylation

“…Hypoxic stress and HIF-1α overexpression have been related to reactive oxygen species (ROS) production. 34,35 Moreover, there are huge evidences showing that H 2 0 2 emission from mitochondria during hypoxia regulates cellular responses to hypoxia. 36,37 In agreement with previous data, results from the present study showed that one of the phenotypic changes that hypoxia induces in hVSMC is an increased ROS production.…”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…[77][78][79][80][81][83][84][85][86] Long-term exposure to these recurrent episodes of hypoxiareoxygenation activate nicotinamide adenine dinucleotide phosphate-oxidase 2 that consumes oxygen through its generation of reactive oxygen species. [287][288][289][290][291] Tissue damage effected by these species is augmented by intermittent hypoxia reducing renal expression of antioxidants. 292 In addition, intermittent hypoxia induces the sympathetic nervous system to increase vascular resistance, downregulates expression of the kallikrein-kallistatin vasodilator Shelley Transforming growth factor β inhibition 446 Pro-fibrotic metalloproteinase inhibition 447 Anti-fibrotic metalloproteinase activation 447 Destabilization of renal Remote ischemic pre-conditioning [384][385][386][387][388][389][390] hypoxia-inducible factor Prolyl hydroxylase inhibition 244,448 von Hippel-Lindau protein inhibition 449 pathway, and activates the renal renin-angiotensin-aldosterone system to cause vasoconstriction.…”