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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases / antagonists & inhibitors
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AMP-Activated Protein Kinases / metabolism
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Acetyl-CoA Carboxylase / metabolism
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Animals
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Carotid Artery Injuries / drug therapy*
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Carotid Artery Injuries / enzymology
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Carotid Artery Injuries / pathology
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Carotid Stenosis / drug therapy*
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Carotid Stenosis / enzymology
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Carotid Stenosis / pathology
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Cell Cycle / drug effects
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Cell Proliferation / drug effects*
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Enzyme Activation
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Enzyme Activators / pharmacology*
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Enzyme Activators / toxicity
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Enzyme Inhibitors / pharmacology
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HeLa Cells
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Humans
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Hyperplasia
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Male
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Muscle, Smooth, Vascular / drug effects*
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Muscle, Smooth, Vascular / enzymology
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Muscle, Smooth, Vascular / pathology
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Myocytes, Smooth Muscle / drug effects*
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Myocytes, Smooth Muscle / enzymology
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Myocytes, Smooth Muscle / pathology
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NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors
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NAD(P)H Dehydrogenase (Quinone) / genetics
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NAD(P)H Dehydrogenase (Quinone) / metabolism*
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Naphthoquinones / pharmacology*
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Naphthoquinones / toxicity
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Phosphorylation
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Platelet-Derived Growth Factor / metabolism
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Protein Serine-Threonine Kinases / metabolism
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RNA Interference
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RNA, Small Interfering / metabolism
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Rats
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Rats, Sprague-Dawley
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Retinoblastoma Protein / metabolism
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Secondary Prevention
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Time Factors
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Tumor Suppressor Protein p53 / metabolism
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Tunica Intima / drug effects
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Tunica Intima / enzymology
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Tunica Intima / pathology
Substances
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Cdkn1a protein, rat
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Cyclin-Dependent Kinase Inhibitor p21
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Enzyme Activators
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Enzyme Inhibitors
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Naphthoquinones
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Platelet-Derived Growth Factor
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RNA, Small Interfering
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Retinoblastoma Protein
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Tumor Suppressor Protein p53
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beta-lapachone
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NAD(P)H Dehydrogenase (Quinone)
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NQO1 protein, human
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NQO1 protein, rat
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Protein Serine-Threonine Kinases
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Stk11 protein, rat
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases
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Acetyl-CoA Carboxylase