TY - JOUR
T1 - Impaired angiotensin II-extracellular signal-regulated kinase signaling in failing human ventricular myocytes
AU - Modesti, Pietro Amedeo
AU - Serneri, Gian Gastone Neri
AU - Gamberi, Tania
AU - Boddi, Maria
AU - Coppo, Mirella
AU - Lucchese, Gianluca
AU - Chiavarelli, Mario
AU - Bottai, Giulia
AU - Marino, Francesco
AU - Toz Gensini, Camilla
AU - Franco Gensini, Gian
AU - Modesti, Alessandra
PY - 2008/10
Y1 - 2008/10
N2 - 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.
AB - 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.
KW - angiotensin II
KW - c-Jun NH-terminal kinase
KW - cardiomyocytes
KW - endothelin-1
KW - extracellular signal-regulated kinase
KW - insulin-like growth factor-1
KW - signaling pathways
UR - http://www.scopus.com/inward/record.url?scp=58149127422&partnerID=8YFLogxK
U2 - 10.1097/HJH.0b013e328308de68
DO - 10.1097/HJH.0b013e328308de68
M3 - Article
C2 - 18806628
AN - SCOPUS:58149127422
SN - 0263-6352
VL - 26
SP - 2030
EP - 2039
JO - Journal of Hypertension
JF - Journal of Hypertension
IS - 10
ER -