B A Markewitz1, I S Farrukh, Y Chen, Y Li, J R Michael. 1. Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Medical Service, Department of Veterans Affairs Medical Center and Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Abstract
OBJECTIVE: Endothelin-1 (ET-1) potently regulates pulmonary vascular tone and promotes vascular smooth muscle cell growth. Clinical and animal studies implicate increased ET-1 production in the pathogenesis of primary and secondary pulmonary hypertension. Although pulmonary arterial smooth muscle cells (PASMCs) synthesize ET-1 under basal conditions, it is unknown whether factors that may be important in pulmonary hypertension, such as transforming growth factor-beta (TGF-beta) or hypoxia, augment ET-1 production by these cells. METHODS: We determined the effect of TGF-beta and hypoxia on ET-1 release and preproET-1 mRNA from cultured rat and human PASMCs. RESULTS: In the basal state, rat and human PASMCs synthesize, on average (mean+/-S.E.M.), 872+/-114 and 563+/-57 pg ET-1/mg cell protein over 24 h, respectively, a level that causes autocrine and paracrine effects in other tissues. TGF-beta significantly increases the expression of preproET-1 mRNA and ET-1 production by both rat and human PASMCs. Hypoxia for 24 h, however, does not affect ET-1 release from rat or human PASMCs. CONCLUSIONS: Cultured rat and human PASMCs are a source of ET-1 production. Enhanced ET-1 release from PASMCs may contribute to the pathophysiology of TGF-beta-induced pulmonary hypertension. ET-1 production by PASMCs is unlikely to contribute to the role of ET-1 in hypoxia-induced pulmonary vasoconstriction.
OBJECTIVE:Endothelin-1 (ET-1) potently regulates pulmonary vascular tone and promotes vascular smooth muscle cell growth. Clinical and animal studies implicate increased ET-1 production in the pathogenesis of primary and secondary pulmonary hypertension. Although pulmonary arterial smooth muscle cells (PASMCs) synthesize ET-1 under basal conditions, it is unknown whether factors that may be important in pulmonary hypertension, such as transforming growth factor-beta (TGF-beta) or hypoxia, augment ET-1 production by these cells. METHODS: We determined the effect of TGF-beta and hypoxia on ET-1 release and preproET-1 mRNA from cultured rat and humanPASMCs. RESULTS: In the basal state, rat and humanPASMCs synthesize, on average (mean+/-S.E.M.), 872+/-114 and 563+/-57 pg ET-1/mg cell protein over 24 h, respectively, a level that causes autocrine and paracrine effects in other tissues. TGF-beta significantly increases the expression of preproET-1 mRNA and ET-1 production by both rat and humanPASMCs. Hypoxia for 24 h, however, does not affect ET-1 release from rat or humanPASMCs. CONCLUSIONS: Cultured rat and humanPASMCs are a source of ET-1 production. Enhanced ET-1 release from PASMCs may contribute to the pathophysiology of TGF-beta-induced pulmonary hypertension. ET-1 production by PASMCs is unlikely to contribute to the role of ET-1 in hypoxia-induced pulmonary vasoconstriction.
Authors: Thomas Bertero; Katherine Cottrill; Adrienn Krauszman; Yu Lu; Sofia Annis; Andrew Hale; Balkrishen Bhat; Aaron B Waxman; B Nelson Chau; Wolfgang M Kuebler; Stephen Y Chan Journal: J Biol Chem Date: 2014-12-12 Impact factor: 5.157
Authors: G G Koliakos; A G P Konstas; U Schlötzer-Schrehardt; G Hollo; D Mitova; D Kovatchev; S Maloutas; N Georgiadis Journal: Br J Ophthalmol Date: 2004-04 Impact factor: 4.638