Details

Autor(en) / Beteiligte

• Kline, David D.
• Peng, Ying-Jie
• Manalo, Dominador J.
• Semenza, Gregg L.
• Prabhakar, Nanduri R.

Titel

Defective Carotid Body Function and Impaired Ventilatory Responses to Chronic Hypoxia in Mice Partially Deficient for Hypoxia-Inducible Factor 1α

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2002-01, Vol.99 (2), p.821-826

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2002

Quelle

MEDLINE

Beschreibungen/Notizen

• 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-1 α subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a+/-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+/-mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a+/-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+/-mice. Thus partial HIF-1α deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.