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First published on July 27, 2005; DOI: 10.1124/mol.105.014449

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Received for publication May 3, 2005.
Revised July 9, 2005.
Accepted for publication July 27, 2005.

Nitric Oxide Inhibits Endothelin-1-induced Cardiomyocyte Hypertrophy through cGMP-mediated Suppression of Extracellular-signal Regulated Kinase Phosphorylation

Tzu-Hurng Cheng 1, Neng-Lang Shih 2, Shin-Yee Chen 3, Jia-Wei Lin 1, Yen-Ling Chen 4, Cheng-Hsien Chen 5, Heng Lin 4, Ching-Feng Cheng 6, Wen-Ta Chiu 7, Danny Ling Wang 8, Jin-Jer Chen 9*

1 Taipei Medical University - Wang Fang Medical Center 2 Department of Life Science, National University of Kaohsiung, Kaohsiung, Taiwan 3 University of British Columbia, Vancouver, British Columbia, Canada 4 Institute of Biomedical Sciences, Academia Sinica, 5 Department of Medicine, Taipei Medical University-Wan Fang Medical Center, Taipei, Taiwan 6 Department of Pediatrics, Tzu Chi Buddhist General Hospital, Hualien, Taiwan 7 Department of Medicine, Taipei Medical University-Wan Fang Medical Center, 8 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 9 National Taiwan University Hospital and National Taiwan University College of Medicine

* Address correspondence to: E-mail: jamesjc{at}ibms.sinica.edu.tw

Abstract

Cardiac hypertrophy is a compensatory mechanism in response to a variety of cardiovascular diseases. Recently, reactive oxygen species and nitric oxide (NO) have been demonstrated to be involved in the pathogenesis of atherosclerosis; however, the role of these free radicals in the development of cardiac hypertrophy remains unclear. Here, we investigate NO modulation of cellular signaling in endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy in culture. ET-1 treatment of cardiomyocytes increased constitutive NO synthase activity and induced NO production via the stimulation of ET-receptor subtype ETB. Using Northern blot analysis and chloramphenicol acetyltransferase assay, we found that NO suppressed the ET-1-induced increase in c-fos mRNA level and promoter activity. In contrast, ET-1 stimulation of c-fos expression was augmented by depletion of endogenous NO generation with the addition of NO scavenger PTIO into cardiomyocytes. Cells cotransfected with the dominant negative and positive mutants of signaling molecules revealed that the Ras/Raf/extracellular-signal regulated kinase (ERK) signaling pathway is involved in ET-induced c-fos gene expression. Furthermore, NO directly inhibited ET-1-induced ERK phosphorylation and activation in a cGMP-dependent manner, indicating that NO modulates ET-1-induced c-fos expression via its inhibitory effect on ERK signaling pathway. The ET-1-stimulated activator protein-1 (AP-1) DNA binding activity and AP-1-mediated reporter activity were attenuated by NO. In addition, NO also significantly inhibited ET-1-stimulated promoter activity of hypertrophic marker gene {beta}-myosin heavy chain and the enhanced protein synthesis. Taken together, our findings provide the molecular basis of NO as a negative regulator in ET-1-induced cardiac hypertrophy.


Key words: Endothelin, Nitric oxide


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