Docosahexaenoic acid monoacylglyceride decreases endothelin-1 induced Ca 2+ sensitivity and proliferation in human pulmonary arteries

Abstract

Background Pulmonary artery vasoconstriction and vascular remodeling contribute to a sustained elevation of pulmonary vascular resistance and pressure in patients with pulmonary arterial hypertension (PH), an often fatal hemodynamic disease. The effect of docosahexaenoic acid monoacylglyceride (MAG-DHA) and the role of the 17 kDa protein kinase C-potentiated inhibitor protein (CPI-17) were determined on vasoconstriction and smooth muscle cell proliferation of human pulmonary arteries (HPA).MethodsHPA were obtained from 16 patients undergoing lung resection for carcinoma. The mechanical tension and Ca 2+ sensitivity were measured on arterial rings treated with endothelin-1 (ET-1) in the absence or presence of MAG-DHA. The effect of MAG-DHA on the level of proliferation of smooth muscle cells isolated from HPA was evaluated in order to determine the role of CPI-17 protein.Results MAG-DHA treatment decreased the reactivity and Ca 2+ sensitivity induced by ET-1 in HPA. MAG-DHA treatment also decreased the expression of vascular endothelial growth factor (VEGF) induced by ET-1. Moreover, both VEGF inhibitor and MAG-DHA treatments reduced Ca 2+ hypersensitivity induced by ET-1, which was associated to a reduction in CPI-17 and myosin-binding subunit of the myosin light chain phosphatase (MYPT-1) phosphorylation levels. Proliferation of ET-1-stimulated HPA smooth muscle cells (PASMc) was also decreased following CPI-17 small interfering RNA transfection and MAG-DHA treatments. Western blot analyses revealed that MAG-DHA treatment resulted in decreased phosphorylation levels of CPI-17 and extracellular signal-regulated kinases (ERK) in PASMc treated with ET-1.ConclusionsWe have demonstrated that VEGF interacts with CPI-17 signaling pathway resulting in an increase in Ca 2+ sensitivity and proliferation of PASMc, whereas MAG-DHA treatment reversed these effects. © 2012 American Journal of Hypertension, Ltd.