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BASIC RESEARCH

Involvement of reactive oxygen species in angiotensin II-induced endothelin-1 gene expression in rat cardiac fibroblasts

Tzu-Hurng Cheng, PhD^*, Pao-Yun Cheng, MS, Neng-Lang Shih, PhD, Iuan-Bor Chen, BS^||, Danny Ling Wang, PhD and Jin-Jer Chen, MD^,*

^* Department of Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, R.O.C.
^|| Present address: Faculty of Art and Science, University of Toronto, Toronto, Ontario, Canada

Manuscript received May 27, 2003; accepted June 4, 2003.

^* Reprint requests and correspondence: Dr. Jin-Jer Chen, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, R.O.C.
thcheng{at}gate.sinica.edu.tw

Presented at the International Young Investigator Prize Symposium at the XIVthWorld Congress of Cardiology.

OBJECTIVES: The aim of this study was to investigate the effects of angiotensin II (Ang II) on fibroblast proliferation and endothelin-1 (ET-1) gene induction, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts.

BACKGROUND: Angiotensin II increases ET-1 expression, which plays an important role in Ang II-induced fibroblast proliferation. Angiotensin II also stimulates ROS generation in cardiac fibroblasts. However, whether ROS are involved in Ang II-induced proliferation and ET-1 expression remains unknown.

METHODS: Cultured neonatal rat cardiac fibroblasts were stimulated with Ang II, and then [³H]thymidine incorporation and the ET-1 gene expression were examined. We also examined the effects of antioxidants on Ang II-induced proliferation and mitogen-activated protein kinase (MAPK) phosphorylation to elucidate the redox-sensitive pathway in fibroblast proliferation and ET-1 gene expression.

RESULTS: Both AT₁ receptor antagonist (losartan) and ET_A receptor antagonist (BQ485) inhibited Ang II-increased DNA synthesis. Endothelin-1 gene was induced with Ang II as revealed by Northern blotting and promoter activity assay. Angiotensin II increased intracellular ROS levels, which were inhibited with losartan and antioxidants. Antioxidants further suppressed Ang II-induced ET-1 gene expression, DNA synthesis, and MAPK phosphorylation. PD98059, but not SB203580, fully inhibited Ang II-induced ET-1 expression. Truncation and mutational analysis of the ET-1 gene promoter showed that AP-1 binding site was an important cis-element in Ang II-induced ET-1 gene expression.

CONCLUSIONS: Our data suggest that ROS are involved in Ang II-induced proliferation and ET-1 gene expression. Our findings imply that the combination of AT_I and ET_A receptor antagonists plus antioxidants may be beneficial in preventing the formation of excessive cardiac fibrosis.

Abbreviations and Acronyms   Ang II = angiotensin II   AP-1 = activator protein-1   AT1 = angiotensin II type 1 receptor   CAT = chloramphenicol acetyltransferase   DCF-DA = dichlorofluorescin diacetate   DPI = diphenyleneiodonium   ECM = extracellular matrix   ERK = extracellular signal-regulated kinase   ETA = ET-1 type A receptor   ET-1 = endothelin-1   GPCRs = G-protein coupled receptors   JNK = c-Jun N-terminal kinase   MAPK = mitogen-activated protein kinase   MEK = MAPK/ERK kinase   mRNA = messenger RNA   NAC = N-acetylcysteine   redox = cellular oxidation reduction   ROS = reactive oxygen species

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