Impaired angiotensin II-extracellular signal-regulated kinase signaling in failing human ventricular myocytes

Pietro Amedeo Modesti, Gian Gastone Neri Serneri, Tania Gamberi, Maria Boddi, Mirella Coppo, Gianluca Lucchese, Mario Chiavarelli, Giulia Bottai, Francesco Marino, Camilla Toz Gensini, Gian Franco Gensini, Alessandra Modesti

Research output: Contribution to journalArticle

Abstract

Angiotensin II was reported to induce insulin-like growth factor-I and endothelin-1 gene expression and peptide release by ventricular cardiomyocytes. However, the progression from cardiac hypertrophy to failure in humans is characterized by a reduced myocyte expression of insulin-like growth factor-I and endothelin-1, notwithstanding the enhanced cardiac generation of angiotensin II. In the present study we investigated the functional status of the signaling pathways responsible for angiotensin II-induced endothelin-1 and insulin-like growth factor-I formation in human ventricular myocytes isolated from patients with dilated (n = 19) or ischemic (n = 14) cardiomyopathy and nonfailing donor hearts (n = 6).In human nonfailing ventricular myocytes, angiotensin II (100 nmol/l) induced insulin-like growth factor-I and endothelin-1 gene expression, and peptide release was mediated by extracellular signal-regulated kinase activation and inhibited by extracellular signal-regulated kinase antagonism (PD98059, 30 μmol/l), endothelin-1 formation being partially reduced also by c-Jun N-terminal kinase inhibition (SP600125, 10 μmol/l); insulin-like growth factor-I and endothelin-1 formations were unaffected by the inhibition of p38 mitogen-activated protein kinase (SB203580, 10 μmol/l) and Janus tyrosine kinase 2 (AG490, 10 μmol/l). In failing myocytes, angiotensin II failed to induce insulin-like growth factor-I and endothelin-1 formation; angiotensin II-induced extracellular signal-regulated kinase activation was significantly impaired (-88% vs. controls) although c-Jun NH2-terminal kinase activation was preserved. The impaired extracellular signal-regulated kinase phosphorylation in failing myocytes was associated with increased myocyte levels of mitogen-activated protein kinase phosphatases.Therefore, the altered growth factor production in failing myocytes is associated with a significant derangement in intracellular signaling.

Original languageEnglish
Pages (from-to)2030-2039
Number of pages10
JournalJournal of Hypertension
Volume26
Issue number10
DOIs
Publication statusPublished - Oct 2008

Keywords

  • angiotensin II
  • c-Jun NH-terminal kinase
  • cardiomyocytes
  • endothelin-1
  • extracellular signal-regulated kinase
  • insulin-like growth factor-1
  • signaling pathways

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Modesti, P. A., Serneri, G. G. N., Gamberi, T., Boddi, M., Coppo, M., Lucchese, G., Chiavarelli, M., Bottai, G., Marino, F., Toz Gensini, C., Franco Gensini, G., & Modesti, A. (2008). Impaired angiotensin II-extracellular signal-regulated kinase signaling in failing human ventricular myocytes. Journal of Hypertension, 26(10), 2030-2039. https://doi.org/10.1097/HJH.0b013e328308de68