title: Activation of NAD(P)H:quinone oxidoreductase 1 prevents arterial restenosis by suppressing vascular smooth muscle cell proliferation.
abstract: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are important pathogenic mechanisms in atherosclerosis and restenosis after vascular injury. In this study, we investigated the effects of beta-lapachone (betaL) (3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione), which is a potent antitumor agent that stimulates NAD(P)H:quinone oxidoreductase (NQO)1 activity, on neointimal formation in animals given vascular injury and on the proliferation of VSMCs cultured in vitro. betaL significantly reduced the neointimal formation induced by balloon injury. betaL also dose-dependently inhibited the FCS- or platelet-derived growth factor-induced proliferation of VSMCs by inhibiting G(1)/S phase transition. betaL increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase 1 in rat and human VSMCs. Chemical inhibitors of AMPK or dominant-negative AMPK blocked the betaL-induced suppression of cell proliferation and the G(1) cell cycle arrest, in vitro and in vivo. The activation of AMPK in VSMCs by betaL is mediated by LKB1 in the presence of NQO1. Taken together, these results show that betaL inhibits VSMCs proliferation via the NQO1 and LKB1-dependent activation of AMPK. These observations provide the molecular basis that pharmacological stimulation of NQO1 activity is a new therapy for the treatment of vascular restenosis and/or atherosclerosis which are caused by proliferation of VSMCs.
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
authors.forename: Sun-Yee
authors.initials: SY
authors.lastname: Kim
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Jeoung
authors.forename: Chang Joo
authors.initials: CJ
authors.lastname: Oh
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Han-Jong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Joon-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Surendar
authors.initials: S
authors.lastname: Tadi
authors.forename: Yong-Hyeon
authors.initials: YH
authors.lastname: Yim
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.forename: Seung
authors.initials: S
authors.lastname: Huh
authors.forename: Ki-Nam
authors.initials: KN
authors.lastname: Min
authors.forename: Kyeong-Hoon
authors.initials: KH
authors.lastname: Jeong
authors.forename: Myoung Gyu
authors.initials: MG
authors.lastname: Park
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
authors.forename: Kouichi
authors.initials: K
authors.lastname: Inukai
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016893:Carotid Stenosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology* / Q000633:toxicity; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016160:Retinoblastoma Protein / Q000378:metabolism; D055502:Secondary Prevention; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C507703:NQO1 protein, rat; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase