© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Regulation of endothelin-1 synthesis in human pulmonary arterial smooth muscle cells
effects of transforming growth factor-β and hypoxia
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
* Corresponding author. University of Utah Health Sciences Center, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, 50 N. Medical Drive, Salt Lake City, UT 84132, USA. Tel.: +1-801-581-7806; fax: +1-801-585-3355
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-β (TGF-β) or hypoxia, augment ET-1 production by these cells. Methods: We determined the effect of TGF-β 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-β 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-β-induced pulmonary hypertension. ET-1 production by PASMCs is unlikely to contribute to the role of ET-1 in hypoxia-induced pulmonary vasoconstriction.
KEYWORDS Endothelins; Growth factors; Hypoxia/anoxia; Pulmonary circulation; Smooth muscle
1 Current address: Department of Surgery, Louisiana State University Medical Center, Shreveport, Louisiana, USA.
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