on June 24, 2002
Published online before print June 24, 2002, doi: 10.1161/01.HYP.0000025443.61926.12
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Submitted on December 24, 2001
From the Department of Cardiovascular Medicine (Y.A.-U., N.A., S.S., K.Y.), Course of Medical and Dental Sciences, and the Department of Molecular Medicine (Y.A.-U., A.O., T.T., S.Y.), Atomic Bomb Disease Institute, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki; and Drug Metabolism and Physicochemical Property Research Laboratory (H.K.), Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan. * To whom correspondence should be addressed. E-mail: mikan{at}net2.nagasaki-u.ac.jp.
Abstract—Cardiac fibrosis results from proliferation of interstitial fibroblasts and concomitant increased biosynthesis of extracellular matrix (ECM) components and is often complicated by cardiac hypertrophy. This study was conducted to investigate whether norepinephrine (NE) potentiates transforming growth factor-ß (TGF-ß)--induced cardiac fibrosis. The expression of the cardiac ECM proteins, plasminogen activator inhibitor-1 (PAI-1), fibronectin, and collagen type I, was examined by Western blotting using extracts from neonatal rat primary cardiac fibroblasts. In cardiac fibroblasts, treatment with a combination of NE and TGF-ß1 increased cell proliferation and ECM expression. Luciferase assays were conducted to clarify the effect of NE on TGF-ß signaling. TGF-ß1 (1 ng/mL) increased the specific signaling activity 2-fold, whereas the combination of NE (10 µmol/L) and TGF-ß1 (1 ng/mL) resulted in an approximate 10-fold increase in specific signaling activity. We confirmed that treatment with NE markedly enhances TGF-ß--induced phosphorylation of activating transcription factor 2 (ATF-2). These results indicated that NE has a synergistic effect on TGF-ß signaling. To determine whether this activation by NE was mediated by the TGF-ß1 receptor, we used a dominant negative vector of the TGF-ß1 type II receptor, and the synergistic effects were inhibited. Furthermore, this synergistic effect was attenuated by a specific inhibitor of p38, SB203680. These data indicate that NE enhances cardiac fibrosis through TGF-ß1 post-receptor signaling, predominantly via the p38 MAP kinase pathway.
Revised on February 7, 2002
Norepinephrine Enhances Fibrosis Mediated by TGF-ß in Cardiac Fibroblasts
Yuri Akiyama-Uchida;
Key words: norepinephrine • transforming growth factors • fibrosis • extracellular matrix • calcium channel blockers
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