Role For Pkc Beta In Enhanced Endothelin-1-Induced Pulmonary Vasoconstrictor Reactivity Following Intermittent Hypoxia

Snow JB, Gonzalez Bosc LV, Kanagy NL, Walker BR, Resta TC. Role for PKC beta in enhanced endothelin-1-induced pulmonary vasoconstrictor reactivity following intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol 301: L745-L754, 2011. First published August 12, 2011; doi:10.1152/ajplung.00020.2011.-Intermittent hypoxia (IH) resulting from sleep apnea causes both systemic and pulmonary hypertension. Enhanced endothelin-1 (ET-1)-induced vasoconstrictor reactivity is thought to play a central role in the systemic hypertensive response to IH. However, whether IH similarly increases pulmonary vasoreactivity and the signaling mechanisms involved are unknown. The objective of the present study was to test the hypothesis that IH augments ET-1-induced pulmonary vasoconstrictor reactivity through a PKC beta-dependent signaling pathway. Responses to ET-1 were assessed in endothelium-disrupted, pressurized pulmonary arteries (similar to 150 mu m inner diameter) from eucapnic-IH [(E-IH) 3 min cycles, 5% O-2-5% CO2/air flush, 7 h/day; 4 wk] and sham (air-cycled) rats. Arteries were loaded with fura-2 AM to monitor vascular smooth muscle (VSM) intracellular Ca2+ concentration ([Ca2+](i)). E-IH increased vasoconstrictor reactivity without altering Ca2+ responses, suggestive of myofilament Ca2+ sensitization. Consistent with our hypothesis, inhibitors of both PKC alpha/beta (myr-PKC) and PKC beta (LY-333-531) selectively decreased vasoconstriction to ET-1 in arteries from E-IH rats and normalized responses between groups, whereas Rho kinase (fasudil) and PKC delta (rottlerin) inhibition were without effect. Although E-IH did not alter arterial PKC alpha/beta mRNA or protein expression, E-IH increased basal PKC beta I/II membrane localization and caused ET-1-induced translocation of these isoforms away from the membrane fraction. We conclude that E-IH augments pulmonary vasoconstrictor reactivity to ET-1 through a novel PKC beta-dependent mechanism that is independent of altered PKC expression. These findings provide new insights into signaling mechanisms that contribute to vasoconstriction in the hypertensive pulmonary circulation.