CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction
| Autor: | Wolfgang M. Kuebler, Elena Noe, Christoph Tabeling, Birgitt Gutbier, Norbert Suttorp, Neil M. Goldenberg, Martin Witzenrath, Michael Schaefer, Diana Zabini, Christoph Arenz, Adrienn Krauszman, Liming Wang, Andreas C. Hocke, Richard L. Proia, Jun Yin, Hanpo Yu, Hannes Ranke |
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| Rok vydání: | 2015 |
| Předmět: |
Cystic Fibrosis Transmembrane Conductance Regulator
030204 cardiovascular system & hematology Pharmacology TRPC6 Mice 0302 clinical medicine Hypoxic pulmonary vasoconstriction Hypoxia Lung Rho-associated protein kinase rho-Associated Kinases 0303 health sciences Multidisciplinary biology Coronary Vessels Cystic fibrosis transmembrane conductance regulator Phosphotransferases (Alcohol Group Acceptor) Protein Transport Receptors Lysosphingolipid Sphingomyelin Phosphodiesterase PNAS Plus Sphingosine kinase 1 medicine.symptom Signal transduction Signal Transduction medicine.medical_specialty Hypertension Pulmonary Myocytes Smooth Muscle Pulmonary Artery Ceramides 03 medical and health sciences Internal medicine TRPC6 Cation Channel medicine Animals Humans Mice Inbred CFTR Calcium Signaling TRPC Cation Channels 030304 developmental biology Hypoxia (medical) respiratory tract diseases Mice Inbred C57BL Oxygen Endocrinology Vasoconstriction Type C Phospholipases biology.protein Calcium |
| Zdroj: | Proceedings of the National Academy of Sciences. 112 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1421190112 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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