Circulation Research. 2001;89:661-669
Published online before print September 27, 2001, doi: 10.1161/hh2001.098873
Published online before print September 27, 2001, doi: 10.1161/hh2001.098873
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© 2001 American Heart Association, Inc.
Molecular Medicine |
ERK and p38 MAPK, but not NF-
B, Are Critically Involved in Reactive Oxygen Species–Mediated Induction of IL-6 by Angiotensin II in Cardiac Fibroblasts
From the Cardiopulmonary Division, Department of Internal Medicine (M. Sano, T.S., S.O.); the Institute for Advanced Cardiac Therapeutics (K.F., H.K.); the Department of Biochemistry (M. Suematsu); the Department of Microbiology and Immunology (S.M., S.K.), Keio University School of Medicine, Shinjuku, Tokyo, Japan; the Department of Molecular Medicine (H.M., K.Y.-T.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan; and the Department of Medicine and Clinical Science (M.H., Y.S.), Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Correspondence to Keiichi Fukuda, MD, Ph.D, Institute for Advanced Cardiac Therapeutics, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail kfukuda{at}sc.itc.keio.ac.jp
Abstract—— We recently reported that angiotensin II (Ang II) induced IL-6 mRNA expression in cardiac fibroblasts, which played an important role in Ang II–induced cardiac hypertrophy in paracrine fashion. The present study investigated the regulatory mechanism of Ang II–induced IL-6 gene expression, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts. Ang II increased intracellular ROS in cardiac fibroblasts, and the increase was completely inhibited by the AT-1 blocker candesartan and the NADH/NADPH oxidase inhibitor diphenyleneiodonium (DPI). We first confirmed that antioxidant N-acetylcysteine, superoxide scavenger Tiron, and DPI suppressed Ang II–induced IL-6 expression. Because we observed that exogenous H2O2 also increased IL-6 mRNA, the signaling pathways downstream of Ang II and exogenous H2O2 were compared. Ang II, as well as exogenous H2O2, activated ERK, p38 MAPK, and JNK, which were significantly inhibited by N-acetylcysteine and DPI. In contrast with exogenous H2O2, however, Ang II did not influence phosphorylation and degradation of I
B-
/ß or nuclear translocation of p65, nor did it increase NF-B promoter activity. PD98059 and SB203580 inhibited Ang II–induced IL-6 expression. Truncation and mutational analysis of the IL-6 gene promoter showed that CRE was an important cis-element in Ang II–induced IL-6 gene expression. NF-B–binding site was important for the basal expression of IL-6, but was not activated by Ang II. Ang II phosphorylated CREB through the ERK and p38 MAPK pathway in a ROS-sensitive manner. Collectively, these data indicated that Ang II stimulated ROS production via the AT1 receptor and NADH/NADPH oxidase, and that these ROS mediated activation of MAPKs, which culminated in IL-6 gene expression through a CRE-dependent, but not NF-B–dependent, pathway in cardiac fibroblasts.
Key Words: angiotensin II • interleukin-6 • reactive oxygen species • mitogen-activated protein kinase • cardiac fibroblast
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