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Originally published In Press as doi:10.1074/jbc.M003128200 on June 7, 2000

J. Biol. Chem., Vol. 275, Issue 38, 29717-29723, September 22, 2000
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Interleukin-6 Family of Cytokines Mediate Angiotensin II-induced Cardiac Hypertrophy in Rodent Cardiomyocytes*

Motoaki SanoDagger , Keiichi FukudaDagger §, Hiroaki KodamaDagger , Jing PanDagger , Mikiyoshi Saito, Junichi Matsuzaki, Toshiyuki TakahashiDagger , Shinji MakinoDagger , Takahiro KatoDagger , and Satoshi OgawaDagger

From the Dagger  Cardiopulmonary Division, Department of Internal Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 and  Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotenba, Shizuoka 412-8513, Japan

This study was designed to investigate whether angiotensin II induces the interleukin (IL)-6 family of cytokines in cardiac fibroblasts and, if so, whether these cytokines can augment cardiac hypertrophy. Angiotensin II increased IL-6, leukemia inhibitory factor (LIF) and cardiotrophin-1 mRNA by 6.5-, 10.2-, and 2.0-fold, respectively, but did not affect IL-11, ciliary neurotrophic factor, or oncostatin M in cardiac fibroblasts. Enzyme-linked immunosorbent assay revealed that angiotensin II-stimulated conditioned medium from cardiac fibroblasts contained 9.3 ng/ml IL-6 at 24 h, which was 24-fold higher than the control. It phosphorylated gp130 and STAT3 in cardiomyocytes, which was reduced with RX435 (anti-gp130 blocking antibody). It increased [3H]phenylalanine uptake and cell area by 44% and 86% in cardiomyocytes compared with mock medium. RX435 suppressed these increases by 26% and 38%, while TAK044 (endothelin-A/B-R blocker) suppressed them by 52% and 52%, respectively. Antisense oligonucleotides against LIF and cardiotrophin-1 blocked their up-regulation, and attenuated the conditioned medium-induced increase in [3H]phenylalanine uptake by 21% and 13%, respectively. The combination of antisense oligonucleotides to LIF and cardiotrophin-1 decreased their uptake by 33%. These results indicated that angiotensin II induced IL-6, LIF, and cardiotrophin-1 in cardiac fibroblasts, and that these cytokines, particularly LIF and cardiotrophin-1, activated gp130-linked signaling and contributed to angiotensin II-induced cardiomyocyte hypertrophy.

* This work was supported in part by Research Grant JSPS-RFTF97I00201 from the Research for the Future Program of the Japan Society for the Promotion of Science, and by research grants from the Ministry of Education, Science and Culture, Japan, Health Science Research Grants for Advanced Medical Technology from the Ministry of Welfare, Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom reprint requests should be addressed. Tel.: 81-3-3353-1211 (ext. 62310); Fax: 81-3-5269-3678; E-mail: kfukuda@mc.med.keio.ac.jp.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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