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Regulation of hypoxia-inducible factor-? isoforms and redox state by carotid body
neural activity in rats
#MMPMID24973414
Peng YJ
; Yuan G
; Khan S
; Nanduri J
; Makarenko VV
; Reddy VD
; Vasavda C
; Kumar GK
; Semenza GL
; Prabhakar NR
J Physiol
2014[Sep]; 592
(17
): 3841-58
PMID24973414
show ga
Previous studies reported that chronic intermittent hypoxia (CIH) results in an
imbalanced expression of hypoxia-inducible factor-? (HIF-?) isoforms and
oxidative stress in rodents, which may be due either to the direct effect of CIH
or indirectly via hitherto uncharacterized mechanism(s). As neural activity is a
potent regulator of gene transcription, we hypothesized that carotid body (CB)
neural activity contributes to CIH-induced HIF-? isoform expression and oxidative
stress in the chemoreflex pathway. Experiments were performed on adult rats
exposed to CIH for 10 days. Rats exposed to CIH exhibited: increased HIF-1? and
decreased HIF-2? expression; increased NADPH oxidase 2 and decreased superoxide
dismutase 2 expression; and oxidative stress in the nucleus tractus solitarius
and rostral ventrolateral medulla as well as in the adrenal medulla (AM), a major
end organ of the sympathetic nervous system. Selective ablation of the CB
abolished these effects. In the AM, sympathetic activation by the CB chemoreflex
mediates CIH-induced HIF-? isoform imbalance via muscarinic acetylcholine
receptor-mediated Ca(2+) influx, and the resultant activation of mammalian target
of rapamycin pathway and calpain proteases. Rats exposed to CIH presented with
hypertension, elevated sympathetic activity and increased circulating
catecholamines. Selective ablation of either the CB (afferent pathway) or
sympathetic innervation to the AM (efferent pathway) abolished these effects.
These observations uncover CB neural activity-dependent regulation of HIF-?
isoforms and the redox state by CIH in the central and peripheral nervous systems
associated with the chemoreflex.
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