title: Impaired angiotensin II-extracellular signal-regulated kinase signaling in failing human ventricular myocytes.
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 micromol/l), endothelin-1 formation being partially reduced also by c-Jun N-terminal kinase inhibition (SP600125, 10 micromol/l); insulin-like growth factor-I and endothelin-1 formations were unaffected by the inhibition of p38 mitogen-activated protein kinase (SB203580, 10 micromol/l) and Janus tyrosine kinase 2 (AG490, 10 micromol/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.
authors.affiliation: Department of Critical Care Medicine, University of Florence, Florence, Italy. pamodesti@unifi.it
authors.forename: Pietro Amedeo
authors.initials: PA
authors.lastname: Modesti
authors.forename: Gian Gastone Neri
authors.initials: GG
authors.lastname: Serneri
authors.forename: Tania
authors.initials: T
authors.lastname: Gamberi
authors.forename: Maria
authors.initials: M
authors.lastname: Boddi
authors.forename: Mirella
authors.initials: M
authors.lastname: Coppo
authors.forename: Gianluca
authors.initials: G
authors.lastname: Lucchese
authors.forename: Mario
authors.initials: M
authors.lastname: Chiavarelli
authors.forename: Giulia
authors.initials: G
authors.lastname: Bottai
authors.forename: Francesco
authors.initials: F
authors.lastname: Marino
authors.forename: Camilla
authors.initials: C
authors.lastname: Toz Gensini
authors.forename: Gian
authors.initials: G
authors.lastname: Franco Gensini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Modesti
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D048049:Extracellular Signal-Regulated MAP Kinases