4.5 Article

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

期刊

JOURNAL OF HYPERTENSION
卷 26, 期 10, 页码 2030-2039

出版社

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HJH.0b013e328308de68

关键词

angiotensin II; cardiomyocytes; c-Jun NH2-terminal kinase; endothelin-1; extracellular signal-regulated kinase; insulin-like growth factor-1; signaling pathways

资金

  1. Ministero dell'Universita' e della Ricerca Scientifica e Tecnologica [003063257-006]
  2. University of Florence [239]

向作者/读者索取更多资源

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 mu mol/l), endothelin-1 formation being partially reduced also by c-Jun N-terminal kinase inhibition (SP600125, 10 mu mol/l); insulin-like growth factor-I and endothelin-1 formations were unaffected by the inhibition of p38 mitogen-activated protein kinase (SB203580, 10 mu mol/l) and Janus tyrosine kinase 2 (AG490, 10 mu mol/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 (S88% 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.

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