Regulation of HIF‐alpha isoform expression and redox state by carotid body chemosensory reflex (710.5)

The carotid body (CB) chemosensory reflex regulates breathing and sympathetic activity during hypoxia. Here, we determined mechanisms underlying regulation of cardio‐vascular function by chemosensory reflex using a rat model of chronic intermittent hypoxia (CIH). Rats exposed to CIH exhibited hypertension and elevated sympathetic activity; these effects were associated with increased HIF‐1α, decreased HIF‐2α expression, and oxidative stress in brainstem regions that regulate sympathetic nervous system. Systemic, cellular and molecular effects of CIH in brainstem were abolished by selective ablation of the CB. CIH exposed adrenal medulla (AM), a major end organ of the sympathetic nervous system also exhibited imbalanced expressions of HIF‐α isoforms and oxidative stress. Selective ablation of CB or sympathetic innervation to the AM abolished these effects. Analysis of the mechanisms in the AM revealed that activation of mTOR pathway and Ca 2+ activated calpain proteases by Ca 2+ signaling coupled to muscarinic acetylcholine receptors (mAChR) contribute to increased HIF‐1α and decreased HIF‐2α expression, respectively. These observations demonstrate a novel reflex regulation of HIF‐α isoforms expression and redox state by the CB, which contributes to regulation of cardio‐vascular function during CIH (Supported by NIH‐HLBI PO1 NIH‐HL‐090554). Grant Funding Source : NIH‐HLBI‐P01HL‐090554