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Role for Nuclear Factor-B and Signal Transducer and Activator of Transcription 1/Interferon Regulatory Factor-1 in Cytokine-Induced Endothelin-1 Release in Human Vascular Smooth Muscle Cells

Department of Cardiac, Vascular, and Inflammation Research, The William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, United Kingdom (M.W., E.G.W., S.C.B., D.B.B., T.D.W.); Department of Critical Care Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom (S.J.W., J.A.); and The School of Biological Sciences, Queen Mary, University of London, London, United Kingdom (S.B.)

Endothelin-1 (ET-1) is a potent vasoconstrictor and growth-promoting mediator that is involved in the maintenance of vascular tone within the healthy circulation. However, a pathogenic role has been implicated by its overproduction in a number of cardiovascular diseases, which include pulmonary hypertension, congestive heart failure, atherosclerosis, and coronary vasospasm. ET-1 mRNA expression and peptide production in human vascular smooth muscle cells (HVSMCs) are markedly increased by exposure to tumor necrosis factor- and interferon-. The intracellular signaling mechanism involved in this pathway is not known. Because the transcription factors nuclear factor-B (NF-B), signal transducer and activator of transcription 1 (STAT1), and interferon regulatory factor-1 (IRF-1) often mediate the effects of cytokines in target cells the aim of this study was to determine whether the production of ET-1 after exposure of HVSMCs to cytokines depends upon synergism between NF-B and STAT1/IRF-1. Immunoblotting showed that cytokine-stimulation of ET-1 release in VSMCs involves nuclear translocation of NF-B and STAT1. Cytokines also induced an increase in IRF-1 protein expression. Antisense oligonucleotides to NF-B, STAT1, and IRF-1 significantly inhibited cytokine induced ET-1 release. In conclusion, NF-B, STAT1, and IRF-1 activation are involved in the stimulation by cytokines of ET-1 release from HVSMCs. However, nuclear run-on assays would provide definitive proof that ET-1 is regulated transcriptionally by cytokines. Because up-regulated production of ET-1 within VSMCs may underlie the causative role of ET-1 in a number of disease states, this finding indicates that NF-B, STAT1, and IRF-1 within HVSMCs could be central to a number of vascular pathologies and that inhibition of this pathway could be of therapeutic benefit.

Address correspondence to: Dr. Mandy Woods, Department of Cardiac, Vascular and Inflammation Research, The William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK. E-mail address: m.p.woods{at}mds.qmw.ac.uk

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