Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension
Proceedings of the National Academy of Sciences, 2011•National Acad Sciences
Cardiorespiratory functions in mammals are exquisitely sensitive to changes in arterial O2
levels. Hypoxia-inducible factors (eg, HIF-1 and HIF-2) mediate transcriptional responses to
reduced oxygen availability. We demonstrate that haploinsufficiency for the O2-regulated
HIF-2α subunit results in augmented carotid body sensitivity to hypoxia, irregular breathing,
apneas, hypertension, and elevated plasma norepinephrine levels in adult Hif-2α+/− mice.
These dysregulated autonomic responses were associated with increased oxidative stress …
levels. Hypoxia-inducible factors (eg, HIF-1 and HIF-2) mediate transcriptional responses to
reduced oxygen availability. We demonstrate that haploinsufficiency for the O2-regulated
HIF-2α subunit results in augmented carotid body sensitivity to hypoxia, irregular breathing,
apneas, hypertension, and elevated plasma norepinephrine levels in adult Hif-2α+/− mice.
These dysregulated autonomic responses were associated with increased oxidative stress …
Cardiorespiratory functions in mammals are exquisitely sensitive to changes in arterial O2 levels. Hypoxia-inducible factors (e.g., HIF-1 and HIF-2) mediate transcriptional responses to reduced oxygen availability. We demonstrate that haploinsufficiency for the O2-regulated HIF-2α subunit results in augmented carotid body sensitivity to hypoxia, irregular breathing, apneas, hypertension, and elevated plasma norepinephrine levels in adult Hif-2α+/− mice. These dysregulated autonomic responses were associated with increased oxidative stress and decreased mitochondrial electron transport chain complex I activity in adrenal medullae as a result of decreased expression of major cytosolic and mitochondrial antioxidant enzymes. Systemic administration of a membrane-permeable antioxidant prevented oxidative stress, normalized hypoxic sensitivity of the carotid body, and restored autonomic functions in Hif-2α+/− mice. Thus, HIF-2α–dependent redox regulation is required for maintenance of carotid body function and cardiorespiratory homeostasis.
National Acad Sciences