Circulation Research. 2001;88:1259-1266
Published online before print June 7, 2001, doi: 10.1161/hh1201.091960
Published online before print June 7, 2001, doi: 10.1161/hh1201.091960
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© 2001 American Heart Association, Inc.
Cellular Biology |
Model for Hypoxic Pulmonary Vasoconstriction Involving Mitochondrial Oxygen Sensing
From the Department of Medicine, The University of Chicago, Chicago, Ill.
Correspondence to Paul T. Schumacker, PhD, Department of Medicine, MC6026, The University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637. E-mail pschumac{at}medicine.bsd.uchicago.edu
Abstract
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
(
0) 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.
Key Words: reactive oxygen species • hypoxia • redox signaling • pulmonary circulation • oxidants
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