ERK and p38 MAPK, but not NF-κB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts

Motoaki Sano, Keiichi Fukuda, Toshihiko Sato, Haruko Kawaguchi, Makoto Suematsu, Satoshi Matsuda, Shigeo Koyasu, Hideo Matsui, Keiko Yamauchi-Takihara, Masaki Harada, Yoshihiko Saito, Satoshi Ogawa

Research output: Contribution to journalArticle

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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 IκB-α/β or nuclear translocation of p65, nor did it increase NF-κB 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-κB-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-κB-dependent, pathway in cardiac fibroblasts.

Original languageEnglish
Pages (from-to)661-669
Number of pages9
JournalCirculation Research
Volume89
Issue number8
Publication statusPublished - 2001 Oct 12

Fingerprint

p38 Mitogen-Activated Protein Kinases
Angiotensin II
Interleukin-6
Reactive Oxygen Species
Fibroblasts
NADPH Oxidase
Acetylcysteine
Gene Expression
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
Messenger RNA
Cardiomegaly
Superoxides
Antioxidants
Binding Sites
Phosphorylation

Keywords

  • Angiotensin II
  • Cardiac fibroblast
  • Interleukin-6
  • Mitogen-activated protein kinase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

ERK and p38 MAPK, but not NF-κB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts. / Sano, Motoaki; Fukuda, Keiichi; Sato, Toshihiko; Kawaguchi, Haruko; Suematsu, Makoto; Matsuda, Satoshi; Koyasu, Shigeo; Matsui, Hideo; Yamauchi-Takihara, Keiko; Harada, Masaki; Saito, Yoshihiko; Ogawa, Satoshi.

In: Circulation Research, Vol. 89, No. 8, 12.10.2001, p. 661-669.

Research output: Contribution to journalArticle

Sano, M, Fukuda, K, Sato, T, Kawaguchi, H, Suematsu, M, Matsuda, S, Koyasu, S, Matsui, H, Yamauchi-Takihara, K, Harada, M, Saito, Y & Ogawa, S 2001, 'ERK and p38 MAPK, but not NF-κB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts', Circulation Research, vol. 89, no. 8, pp. 661-669.
Sano, Motoaki ; Fukuda, Keiichi ; Sato, Toshihiko ; Kawaguchi, Haruko ; Suematsu, Makoto ; Matsuda, Satoshi ; Koyasu, Shigeo ; Matsui, Hideo ; Yamauchi-Takihara, Keiko ; Harada, Masaki ; Saito, Yoshihiko ; Ogawa, Satoshi. / ERK and p38 MAPK, but not NF-κB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts. In: Circulation Research. 2001 ; Vol. 89, No. 8. pp. 661-669.
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AU - Kawaguchi, Haruko

AU - Suematsu, Makoto

AU - Matsuda, Satoshi

AU - Koyasu, Shigeo

AU - Matsui, Hideo

AU - Yamauchi-Takihara, Keiko

AU - Harada, Masaki

AU - Saito, Yoshihiko

AU - Ogawa, Satoshi

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N2 - 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 IκB-α/β or nuclear translocation of p65, nor did it increase NF-κB 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-κB-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-κB-dependent, pathway in cardiac fibroblasts.

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