PKCα Deficiency in Mice Is Associated with Pulmonary Vascular Hyperresponsiveness to Thromboxane A2 and Increased Thromboxane Receptor Expression

Pulmonary vascular hyperresponsiveness is a main characteristic of pulmonary arterial hypertension (PAH). In PAH patients, elevated levels of the vasoconstrictors thromboxane A2 (TXA2), endothelin (ET)-1 and serotonin further contribute to pulmonary hypertension. Protein kinase C (PKC) isozyme alpha (PKC alpha) is a known modulator of smooth muscle cell contraction. However, the effects of PKC alpha deficiency on pulmonary vasoconstriction have not yet been investigated. Thus, the role of PKC alpha in pulmonary vascular responsiveness to the TXA2 analog U46619, ET-1, serotonin and acute hypoxia was investigated in isolated lungs of PKC alpha(-/-) mice and corresponding wild-type mice, with or without prior administration of the PKC inhibitor bisindolylmaleimide I or Go6976. mRNA was quantified from microdissected intrapulmonary arteries. We found that broad-spectrum PKC inhibition reduced pulmonary vascular responsiveness to ET-1 and acute hypoxia and, by trend, to U46619. Analogously, selective inhibition of conventional PKC isozymes or PKCa deficiency reduced ET-1-evoked pulmonary vasoconstriction. The pulmonary vasopressor response to serotonin was unaffected by either broad PKC inhibition or PKC alpha deficiency. Surprisingly, PKC alpha(-/-) mice showed pulmonary vascular hyperresponsiveness to U46619 and increased TXA2 receptor (TP receptor) expression in the intrapulmonary arteries. To conclude, PKC alpha regulates ET-1-induced pulmonary vasoconstriction. However, PKC alpha deficiency leads to pulmonary vascular hyperresponsiveness to TXA2, possibly via increased pulmonary arterial TP receptor expression. (C) 2016 S. Karger AG, Basel