title: Phosphatidylinositol 3-kinase in angiotensin II-induced hypertrophy of vascular smooth muscle cells.
abstract: Activation of 4E-binding protein 1 (4E-BP1) by growth factors regulates protein synthesis in vascular smooth muscle cells. The interaction between G protein-coupled receptors and activated 4E-BP1 is unclear. We examined phosphadityl inositol (PI) 3-kinase in angiotensin II-induced 4E-BP1 phosphorylation in cultured rat vascular smooth muscle cells. Angiotensin II time and dose dependently stimulated phosphorylation of 4E-BP1 through the angiotensin AT(1) receptor. Pretreatment with wortmannin or 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a PI 3-kinase inhibitor, suppressed angiotensin II-induced phosphorylation, but a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) kinase-1 (MEK-1) inhibitor, 2'-Amino-3'-methoxyflavone (PD98059), and a p38 MAPK inhibitor, 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), had no effect. With regard to the involvement of mammalian target of rapamycin (mTOR) and p70 S6 kinase, angiotensin II-induced phosphorylation was abolished by pretreatment with rapamycin, but not by tosylphenylalanine chloromethyl ketone or tosyllysine chloromethyl ketone. Ca(2+) was involved, since intracellular Ca(2+) chelation inhibited angiotensin II-induced phosphorylation while a Ca(2+) ionophore, A23187, stimulated phosphorylation. Thus, angiotensin II induces the phosphorylation of 4E-BP1 via the PI 3-kinase/mTOR pathway, but not via ERK or p70 S6 kinase.
authors.affiliation: Department of Endocrinology and Diabetes, Yokohama City University Medical Center, 4-57 Urafuncecho, Yokohama Minami 232-0024, Japan. yamakat@urahp.yokohama-cu.ac.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamakawa
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Junzo
authors.initials: J
authors.lastname: Kamei
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kadonosono
authors.forename: Kenji
authors.initials: K
authors.lastname: Okuda
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006984:Hypertrophy; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D000804:Angiotensin II; D019869:Phosphatidylinositol 3-Kinases