Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced β-myosin heavy chain gene expression and cardiomyocyte hypertrophy

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

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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 β-MyHC gene expression. ET-1 increased 3H-leucine incorporation and β-MyHC promoter activities, which were blocked by the specific ET A 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 β-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-1-induced AP-2 and SP-1 binding activities were also inhibited by antioxidant. These data demonstrate the involvement of ROS in ET-1-induced hypertrophic responses and β-MyHC expression. ROS mediate ET-1-induced activation of MAPK pathways, which culminates in hypertrophic responses and β-MyHC expression.

Original languageEnglish (US)
Pages (from-to)123-133
Number of pages11
JournalJournal of Biomedical Science
Volume12
Issue number1
DOIs
StatePublished - Jan 2005
Externally publishedYes

Keywords

  • Cardiomyocyte
  • Endothelin-1
  • Hypertrophy
  • Rat
  • Reactive oxygen species
  • β-myosin heavy chain gene

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced β-myosin heavy chain gene expression and cardiomyocyte hypertrophy'. Together they form a unique fingerprint.

Cite this