Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Tabeling, C; Yu, H; Wang, L; Ranke, H; Goldenberg, NM; Zabini, D; Noe, E; Krauszman, A; Gutbier, B; Yin, J; Schaefer, M; Arenz, C; Hocke, AC; Suttorp, N; Proia, RL; Witzenrath, M; Kuebler, WM.
CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction.
Proc Natl Acad Sci U S A. 2015; 112(13):E1614-E1623
Doi: 10.1073/pnas.1421190112
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- Co-Autor*innen der Med Uni Graz
- Zabini-Polzer Diana
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Calcium - metabolism
- Calcium Signaling -
- Ceramides - chemistry
- Coronary Vessels - metabolism
- Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
- Humans -
- Hypertension, Pulmonary - metabolism
- Hypoxia - pathology
- Lung - metabolism
- Lung - pathology
- Mice -
- Mice, Inbred C57BL -
- Mice, Inbred CFTR -
- Myocytes, Smooth Muscle - metabolism
- Oxygen - metabolism
- Phosphotransferases (Alcohol Group Acceptor) - metabolism
- Protein Transport -
- Pulmonary Artery - metabolism
- Receptors, Lysosphingolipid - metabolism
- Signal Transduction -
- Sphingomyelin Phosphodiesterase - metabolism
- TRPC Cation Channels - metabolism
- TRPC6 Cation Channel -
- Type C Phospholipases - metabolism
- Vasoconstriction -
- rho-Associated Kinases - metabolism
- Find related publications in this database (Keywords)
- pulmonary hypertension
- neutral sphingomyelinase
- ceramide
- transient receptor potential canonical 6