title: p38 MAP kinase negatively regulates angiotensin II-mediated effects on cell cycle molecules in human coronary smooth muscle cells.
abstract: Many of the signaling events in VSMC stimulated by angiotensin II (AngII) are mediated by members of the mitogen-activated protein kinase (MAPK) family, including p38 MAPK. The role of p38 MAPK in AngII-mediated cell cycle regulation is poorly understood. Therefore, we examined the involvement of p38 MAPK signaling in AngII-stimulated DNA synthesis, phosphorylation of the retinoblastoma protein (Rb), and expression of the G1-phase cyclin D1 in human coronary artery smooth muscle cells (CASMC). AngII (1 microM) stimulated p38 MAPK and ERK1/2 activation. Pretreatment with the p38 MAPK inhibitors SB203580 (10 microM) (SB) or SKF-86002 (10 microM) (SKF) potently inhibited AngII-induced p38 MAPK activation, but enhanced AngII-mediated ERK1/2 activation. AngII-induced-phosphorylation of Rb (Ser 795 and Ser 807/811), -cyclin D1 expression, and -DNA synthesis was also markedly enhanced by pharmacological inhibition of the p38 MAPK pathway. The present study demonstrates that p38 MAPK negatively regulates AngII-induced ERK1/2 activity, Rb phosphorylation, cyclin D1 expression, and DNA-synthesis in human CASMC. These findings support an important role for p38 MAPK in modulating AngII-mediated VSMC hyperplasia.
authors.affiliation: Institute of Pharmacology and Toxicology, Charité Hospital, Humboldt-University Berlin, D-10117 Berlin, Germany. ulrich.kintscher@charite.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
authors.forename: Florian
authors.initials: F
authors.lastname: Blaschke
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Law
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002453:Cell Cycle; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D016160:Retinoblastoma Protein; D013844:Thiazoles; D000804:Angiotensin II; D019938:Cyclin D1; D004247:DNA; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580