- 作者: Tzu-Hurng Cheng; Neng-Lang Shih; Cheng-Hsien Chen; Heng Lin; Ju-Chi Liu; Hung-Hsing Chao; Jer-Young Liou; Yen-Ling Chen; Hsing-Wen Tsai; Yee-Shiuan Chen; Ching-Feng Cheng; Jin-Jer Chen
- 作者服務機構: 1 Department of Medicine, Taipei Medical University-Wan Fang Hospital; ; 2 Institute of Biomedical Sciences, Academia Sinica; ; 3 Department of Life Science, National University of Kaohsiung, Kaohsiung;; 4 Section of Cardiology, Department of Medicine, Taipei Medical University Hospital; ; 5 Shin Kong Wu Ho-Su Memorial Hospital; ; 6 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
- 中文摘要: --
- 英文摘要: Endothelin-1 (ET-1) has been found to increase cardiac β-myosin heavy chain (β-MyHC) gene expression and induce hypertrophy in cardiomyocytes. ET-1 has been demonstrated to increase intracellular reactive oxygen species (ROS) in cardiomyocytes. The exact molecular mechanism by which ROS regulate ET-1-induced β-MyHC gene expression and hypertrophy in cardiomyocytes, however, has not yet been fully described. We aim to elucidate the molecular regulatory mechanism of ROS on ET-1-induced β-MyHC gene expression and hypertrophic signaling in neonatal rat cardiomyocytes. Following stimulation with ET-1, cultured neonatal rat cardiomyocytes were examined for 3H-leucine incorporation and β-MyHC promoter activities. The effects of antioxidant pretreatment on ET-1-induced cardiac hypertrophy and mitogen-activated protein kinase (MAPKs) phosphorylation were studied to elucidate the redox-sensitive pathway in cardiomyocyte hypertrophy and jS-MyHC gene expression. ET-1 increased 3H-leucine incorporation and β-MyHC promoter activities, which were blocked by the specific ETA receptor antagonist BQ-485. Antioxidants significantly reduced ET-1-induced 3H-leucine incorporation, β-MyHC gene promoter activities and MAPK (extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase) phosphorylation. Both PD98059 and SB203580 inhibited ET-1-increased 3H-leucine incorporation and β-MyHC promoter activities. Co-transfection of the dominant negative mutant of Ras, Raf, and MEK1 decreased the ET-1-induced /J-MyHC promoter activities, suggesting that the Ras-Raf-MAPK pathway is required for ET-1 action. Truncation analysis of the β-MyHC gene promoter showed that the activator protein-2 (AP-2)/specificity protein-1 (SP-1) binding site(s) were(was) important cis-element(s) in ET-1-induced β-MyHC gene expression. Moreover, ET-l-induced AP-2 and SP-1 binding activities were also inhibited by antioxidant. These data demonstrate the involvement of ROS in ET-l-induced hypertrophic responses and β-MyHC expression.
- 中文關鍵字: --
- 英文關鍵字: β-myosin heavy chain gene, cardiomyocyte,endothelin-l, hypertrophy, rat, reactive oxygen species