RT Journal Article
SR Electronic
T1 Cystic fibrosis transmembrane conductance regulator and sphingolipids regulate hypoxic pulmonary vasoconstriction
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA4905
DO 10.1183/13993003.congress-2015.PA4905
VO 46
IS suppl 59
A1 Christoph Tabeling
A1 Hanpo Yu
A1 Liming Wang
A1 Hannes Ranke
A1 Neil M. Goldenberg
A1 Diana Zabini
A1 Elena Noe
A1 Adrienn Krauszman
A1 Birgitt Gutbier
A1 Jun Yin
A1 Michael Schaefer
A1 Christoph Arenz
A1 Andreas C. Hocke
A1 Norbert Suttorp
A1 Richard L. Proia
A1 Martin Witzenrath
A1 Wolfgang M. Kuebler
YR 2015
UL http://erj.ersjournals.com/content/46/suppl_59/PA4905.abstract
AB Background: Gene mutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis, which is associated with profound pulmonary ventilation-perfusion (VA/Q) mismatches. Hypoxic pulmonary vasoconstriction (HPV) minimizes VA/Q inequalities. However, chronic hypoxemia-associated lung diseases frequently result in pulmonary hypertension (PH).Aims and objectives: We hypothesized that CFTR may mediate HPV potentially by modulating the response to sphingolipids as mediators of HPV.Methods: HPV and VA/Q mismatch were analyzed in isolated mouse lungs or in vivo. Ca2+ mobilization, transient receptor potential canonical 6 (TRPC6) translocation to caveolae and the interaction between CFTR and TRPC6 were studied in pulmonary arterial smooth muscle cells (PASMC). The role of CFTR in long-term vascular adaptation to chronic hypoxia was analyzed in CFTR-/- mice.Results: CFTR deficiency diminished HPV, aggravated VA/Q mismatch and partially protected from hypoxic PH. In PASMC, hypoxia caused CFTR/TRPC6 complex formation, while CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca2+ mobilization. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, while exogenous nSMase caused CFTR-dependent TRPC6 translocation and vasoconstriction. 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 vasoconstriction that involved TRPC6, phospholipase C, and rho kinase.Conclusions: These findings demonstrate a central role of CFTR and sphingolipids in HPV.