TY - JOUR
T1 - Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α
AU - Kline, David D.
AU - Peng, Ying Jie
AU - Manalo, Dominador J.
AU - Semenza, Gregg L.
AU - Prabhakar, Nanduri R.
PY - 2002/1/22
Y1 - 2002/1/22
N2 - To investigate whether the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for ventilatory responses to hypoxia, we analyzed mice that were either wild type or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus, which encodes the O2-regulated HIF-1α subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a+1- mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body chemoreceptors played a predominant role. When carotid bodies isolated from wild-type mice were exposed to either cyanide or hypoxia, a marked increase in sinus nerve activity was recorded, whereas carotid bodies from Hif1a+1- mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a+1- mice. Wild-type mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in Hif1a+1- mice. Thus partial HIF-1 α deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.
AB - To investigate whether the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for ventilatory responses to hypoxia, we analyzed mice that were either wild type or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus, which encodes the O2-regulated HIF-1α subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a+1- mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body chemoreceptors played a predominant role. When carotid bodies isolated from wild-type mice were exposed to either cyanide or hypoxia, a marked increase in sinus nerve activity was recorded, whereas carotid bodies from Hif1a+1- mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a+1- mice. Wild-type mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in Hif1a+1- mice. Thus partial HIF-1 α deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.
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U2 - 10.1073/pnas.022634199
DO - 10.1073/pnas.022634199
M3 - Article
C2 - 11792862
AN - SCOPUS:0037154262
SN - 0027-8424
VL - 99
SP - 821
EP - 826
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 2
ER -