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Role of CFTR and sphingolipids in hypoxic pulmonary vasoconstriction
Author(s) -
Yu Hanpo,
Wang Liming,
Kapus Andras,
Kuebler Wolfgang M.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.700.3
Subject(s) - hypoxic pulmonary vasoconstriction , trpc6 , caveolae , cystic fibrosis transmembrane conductance regulator , sphingolipid , cystic fibrosis , hypoxia (environmental) , lung , vasoconstriction , sphingomyelin , chemistry , microbiology and biotechnology , perfusion , biology , signal transduction , endocrinology , medicine , biochemistry , transient receptor potential channel , receptor , cholesterol , organic chemistry , oxygen
Background Hypoxic pulmonary vasoconstriction (HPV) optimizes ventilation‐perfusion matching in the lung. As cystic fibrosis patients suffer from ventilation‐perfusion mismatches, we probed for a potential role of cystic fibrosis transmembrane conductance regulator (CFTR) in HPV. Methods HPV was quantified in isolated lungs as increase in perfusion pressure in response to hypoxia. In cultured human pulmonary artery smooth muscle cells (PASMC), Ca 2+ concentration ([Ca 2+ ] i ) was imaged, and caveolae were isolated and probed for translocated Ca 2+ entry channels. Results HPV was attenuated by CFTR inhibitors or in lungs of CFTR −/− mice. In PASMC, CFTR inhibition blocked the hypoxia‐induced [Ca 2+ ] i increase and the caveolar translocation of TRPC6 channels. CFTR's role in HPV was not attributable to Cl − transport, as modulation of extracellular Cl − did not alter HPV. Instead, the role of CFTR was related to sphingolipid signaling in HPV. In isolated lungs, inhibition of either neutral sphingomyelinase (SMase) or sphingosine kinase attenuated HPV. Exogenous SMase mimicked hypoxia, in that it caused pulmonary vasoconstriction, increased PASMC [Ca 2+ ] i , and translocated TRPC6 to caveolae, yet responses to SMase were blocked by CFTR inhibition. Conclusion Our findings identify a critical role for CFTR in HPV that relates to sphingolipid signaling by a mechanism currently under investigation.