RT Journal Article
SR Electronic
T1 PKCα deficiency in mice is associated with pulmonary vascular hyperresponsiveness to thromboxane A<sub>2</sub> via increased TXA<sub>2</sub> receptor expression
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P308
VO 44
IS Suppl 58
A1 Christoph Tabeling
A1 Elena Noe
A1 Jan Naujoks
A1 Jan-Moritz Doehn
A1 Stefan Hippenstiel
A1 Bastian Opitz
A1 Norbert Suttorp
A1 Robert Klopfleisch
A1 Martin Witzenrath
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P308.abstract
AB Introduction: Pulmonary vascular hyperresponsiveness is a main characteristic of pulmonary arterial hypertension (PAH) and elevated levels of thromboxane A2 (TXA2) and endothelin-1 (ET-1) in PAH patients have been described. Downstream signaling of TXA2 and ET-1 involves activation of the protein kinase C (PKC) family, and PKC inhibition has been proposed as therapeutic strategy in PAH. However, the effects of PKC isoenzyme alpha deficiency (PKCα-/-) on pulmonary vascular responsiveness have not been investigated.Methods: Pulmonary vascular responsiveness to TXA2 receptor analog U46619 and ET-1 was investigated in isolated perfused and ventilated lungs of PKCα-/- and corresponding wildtype mice (wt), with or without prior administration of pan-PKC inhibitor bisindolylmaleimide. TXA2 receptor and PKC isoenzyme mRNA expression of microdissected pulmonary arteries and whole lung tissue was quantified.Results: Surprisingly, isolated lungs of PKCα-/- mice showed pulmonary vascular hyperresponsiveness to U46619 compared to wt mice, whereas pulmonary vascular responsiveness to ET-1 was reduced in PKCα-/- mice and after pan-PKC inhibition. mRNA analysis showed increased TXA2 receptor expression in PKCα-/- pulmonary arteries compared to wt, while PKC isoenzyme expression was comparable between PKCα-/- and wt.Conclusion: PKCα deficiency was associated with increased pulmonary vascular responsiveness to TXA2 due to increased pulmonary arterial TXA2 receptor expression.