title: Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression.
abstract: Vascular smooth muscle cell (VSMC) proliferation is a critical event in the development and progression of vascular diseases, including atherosclerosis. We investigated whether the activation of adenosine monophosphate-activated protein kinase (AMPK) could suppress VSMC proliferation and inhibit cell cycle progression. Treatment of human aortic smooth muscle cells (HASMCs) or isolated rabbit aortas with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) induced phosphorylation of AMPK and acetyl Co-A carboxylase. AICAR significantly inhibited HASMC proliferation induced by both platelet-derived growth factor-BB (PDGF-BB) and fetal calf serum (FCS). Treatment with AICAR inhibited the phosphorylation of retinoblastoma gene product (Rb) induced by PDGF-BB or FCS, and increased the expression of cyclin-dependent kinase inhibitor p21(CIP) but not that of p27(KIP). Pharmacological inhibition of AMPK or overexpression of dominant negative-AMPK inhibited both the suppressive effect of AICAR on cell proliferation and the phosphorylation of Rb, suggesting that the effect of AICAR is mediated through the activation of AMPK. Cell cycle analysis in HASMCs showed that AICAR significantly increased cell population in G0/G1-phase and reduced that in S- and G2/M-phase, suggesting AICAR induced cell cycle arrest. AICAR increased both p53 protein and Ser-15 phosphorylated p53 in HASMCs, which were blocked by inhibition of AMPK. In isolated rabbit aortas, AICAR also increased Ser-15 phosphorylation and protein expression of p53 and inhibited Rb phosphorylation induced by FCS. These data suggest for the first time that AMPK suppresses VSMC proliferation via cell cycle regulation by p53 upregulation. Therefore, AMPK activation in VSMCs may be a therapoietic target for the prevention of vascular diseases.
authors.affiliation: Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 860-8554, Japan.
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Igata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Motoshima
authors.forename: Kaku
authors.initials: K
authors.lastname: Tsuruzoe
authors.forename: Kanou
authors.initials: K
authors.lastname: Kojima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsumura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kondo
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Taguchi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamaru
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yano
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kukidome
authors.forename: Kazuya
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Toyonaga
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Eiichi
authors.initials: E
authors.lastname: Araki
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D000077214:Becaplermin; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009097:Multienzyme Complexes / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D011817:Rabbits; D016160:Retinoblastoma Protein / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016160:Retinoblastoma Protein; D012265:Ribonucleotides; D016159:Tumor Suppressor Protein p53; D000077214:Becaplermin; D000620:Aminoimidazole Carboxamide; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide