naphthoquinones and Hyperplasia

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.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Carotid Artery Injuries; Carotid Stenosis; Cell Cycle; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators; Enzyme Inhibitors; HeLa Cells; Humans; Hyperplasia; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Phosphorylation; Platelet-Derived Growth Factor; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Retinoblastoma Protein; RNA Interference; RNA, Small Interfering; Secondary Prevention; Time Factors; Tumor Suppressor Protein p53; Tunica Intima

Topics: Animals; Cardiovascular Agents; Carotid Stenosis; Cell Proliferation; Coronary Restenosis; Drug-Eluting Stents; Enzyme Activation; Enzyme Activators; Humans; Hyperplasia; Muscle, Smooth, Vascular; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Secondary Prevention; Tunica Intima

The polyketide antibiotic Frenolicin-B (FB) produces anorexia and esophageal epithelial hyperplasia (EH) in rats, findings that are characteristic of zinc deficiency. Because FB also chelates divalent cations in vitro, we conducted studies to determine whether FB modifies blood and organ concentrations of zinc and other essential metals (calcium, copper, iron and magnesium). Groups of male Sprague-Dawley rats ( approximately 250g; n = 20/group) consumed diets with adequate (40 microg/g), deficient (<2 microg/g) or fortified (100 microg/g) zinc concentrations ad libitum for 28 d. Two groups fed either Zn-adequate or Zn-fortified diets also were given 100 mg/(kg. d) of FB in diet, and 2 groups were pair-fed controls. Histopathology or metal analyses were performed on tissues from 10 rats/group. FB caused EH of the nonglandular stomach but not of other tissues. Of the metals evaluated, only copper concentrations were significantly reduced in all tissues examined except kidney. A broad range of kidney copper concentrations was found; these concentrations were associated with plasma copper and proteinaceous deposits within tubules. In rats, FB substantially and selectively depletes Cu in vivo, suggesting that drugs with structures that permit metal chelation should be evaluated for their potential to alter trace metal nutriture.

Topics: Animals; Anti-Bacterial Agents; Brain Chemistry; Copper; Diet; Epithelium; Esophagus; Femur; Hyperplasia; Iron; Iron Deficiencies; Kidney; Magnesium; Magnesium Deficiency; Naphthoquinones; Organ Size; Rats; Rats, Sprague-Dawley; Salivary Glands; Stomach; Tongue; Zinc