Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing

Gregory B. Waypa, Navdeep S. Chandel, Paul T. Schumacker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

302 Scopus citations

Abstract

We tested whether mitochondria function as the O2 sensor underlying hypoxic pulmonary vasoconstriction (HPV). In buffer-perfused rat lungs, rotenone, myxothiazol, and diphenyleneiodonium, which inhibit mitochondria in the proximal region of the electron transport chain (ETC), abolished HPV without attenuating the response to U46619. Cyanide and antimycin A inhibit electron transfer in the distal region of the ETC, but they did not abolish HPV. Cultured pulmonary artery (PA) myocytes contract in response to hypoxia or to U46619. The hypoxic response was abolished while the response to U46619 was maintained in mutant (ρ0) PA myocytes lacking a mitochondrial ETC. To test whether reactive oxygen species (ROS) derived from mitochondria act as signaling agents in HPV, the antioxidants pyrrolidinedithiocarbamate and ebselen and the Cu,Zn superoxide dismutase inhibitor diethyldithiocarbamate were used. These abolished HPV without affecting contraction to U46619, suggesting that ROS act as second messengers. In cultured PA myocytes, oxidation of intracellular 2′,7′-dichlorofluorescin diacetate (DCFH) dye increased under 2% O2, indicating that myocytes increase their generation of H2O2 during hypoxia. This was attenuated by myxothiazol, implicating mitochondria as the source of increased ROS during HPV. These results indicate that mitochondrial ATP is not required for HPV, that mitochondria function as O2 sensors during hypoxia, and that ROS generated in the proximal region of the ETC act as second messengers in the response.

Original languageEnglish (US)
Pages (from-to)1259-1266
Number of pages8
JournalCirculation research
Volume88
Issue number12
DOIs
StatePublished - Jun 22 2001

Keywords

  • Hypoxia
  • Oxidants
  • Pulmonary circulation
  • Reactive oxygen species
  • Redox signaling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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