title: Requirement of activation of the extracellular signal-regulated kinase cascade in myocardial cell hypertrophy.
abstract: The signal transduction mechanisms mediating hypertrophic responses in myocardial cells (MCs) remain uncertain. We investigated the role of the extracellular signal-regulated kinase (ERK) cascade in myocardial cell hypertrophy by the strategy of using the adenovirus-mediated overexpression of mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), which is the upstream activator of ERK. We generated recombinant adenoviruses expressing constitutively active MEK1 (MEK1 EE) and dominant negative MEK1 (MEK1 DN). Overexpression of MEK1 EE in MCs activated ERK1/2 and subsequently induced atrial natriuretic peptide (ANP) mRNA expression. In addition, MEK1 EE overexpression resulted in an increase in cell size and sarcomeric reorganization. In contrast, overexpression of MEK1 DN in MCs inhibited endothelin-1 (ET-1)-, phenylephrine (PE)-, leukemia inhibitory factor (LIF)-, isoproterenol (ISP)-, and mechanical stretch-induced ERK activation and ANP mRNA expression. MEK1 DN overexpression inhibited ET-1-, PE-, LIF-, and ISP-induced increases in cell size and sarcomeric reorganization. Consistent with the observed effects on cellular morphology, overexpression of MEK1 EE resulted in an increase in amino acid incorporation, while overexpression of MEK1 DN inhibited ET-1-, PE-, LIF-, ISP-, and mechanical stretch-induced increases in amino acid incorporation. These results indicate that the ERK cascade plays an important role in the signaling pathway leading to the development of myocardial cell hypertrophy.
authors.affiliation: The First Department of Internal Medicine, Kobe University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ueyama
authors.forename: S
authors.initials: S
authors.lastname: Kawashima
authors.forename: T
authors.initials: T
authors.lastname: Sakoda
authors.forename: Y
authors.initials: Y
authors.lastname: Rikitake
authors.forename: T
authors.initials: T
authors.lastname: Ishida
authors.forename: M
authors.initials: M
authors.lastname: Kawai
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: S
authors.initials: S
authors.lastname: Ishido
authors.forename: H
authors.initials: H
authors.lastname: Hotta
authors.forename: M
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000256:Adenoviridae; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000201:enzymology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005822:Genetic Vectors; D006984:Hypertrophy; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases