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Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):E1614-23. doi: 10.1073/pnas.1421190112. Epub 2015 Mar 17.

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction.

Author information

1
Departments of Infectious Diseases and Pulmonary Medicine and.
2
Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; The Keenan Research Centre for Biomedical Science of St. Michael's, Toronto, ON M5B 1W8, Canada;
3
The Keenan Research Centre for Biomedical Science of St. Michael's, Toronto, ON M5B 1W8, Canada; Department of Anesthesia, University of Toronto, Toronto, ON M5G 1E2, Canada;
4
The Keenan Research Centre for Biomedical Science of St. Michael's, Toronto, ON M5B 1W8, Canada;
5
Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, 04107 Leipzig, Germany;
6
Institute for Chemistry, Humboldt University, 12489 Berlin, Germany;
7
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and.
8
Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; The Keenan Research Centre for Biomedical Science of St. Michael's, Toronto, ON M5B 1W8, Canada; Departments of Physiology and Surgery, University of Toronto, Toronto, ON M5G 1E2, Canada kueblerw@smh.ca.

Abstract

Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca(2+) mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca(2+) mobilization. Ca(2+) mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.

KEYWORDS:

ceramide; neutral sphingomyelinase; pulmonary hypertension; transient receptor potential canonical 6

PMID:
25829545
PMCID:
PMC4386337
DOI:
10.1073/pnas.1421190112
[Indexed for MEDLINE]
Free PMC Article

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