title: The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia.
abstract: Vascular smooth muscle cell (SMC) migration is regulated by cytoskeletal remodeling as well as by certain transient receptor potential (TRP) channels, nonselective cation channels that modulate calcium influx. Proper function of multiple subfamily C TRP (TRPC) channels requires the scaffolding protein Homer 1, which associates with the actin-binding protein Drebrin. We found that SMC Drebrin expression is upregulated in atherosclerosis and in response to injury and investigated whether Drebrin inhibits SMC activation, either through regulation of TRP channel function via Homer or through a direct effect on the actin cytoskeleton.
  
  
  
  Wild-type (WT) and congenic Dbn(-/+) mice were subjected to wire-mediated carotid endothelial denudation. Subsequent neointimal hyperplasia was 2.4±0.3-fold greater in Dbn(-/+) than in WT mice. Levels of globular actin were equivalent in Dbn(-/+) and WT SMCs, but there was a 2.4±0.5-fold decrease in filamentous actin in Dbn(-/+) SMCs compared with WT. Filamentous actin was restored to WT levels in Dbn(-/+) SMCs by adenoviral-mediated rescue expression of Drebrin. Compared with WT SMCs, Dbn(-/+) SMCs exhibited increased TRP channel activity in response to platelet-derived growth factor, increased migration assessed in Boyden chambers, and increased proliferation. Enhanced TRP channel activity and migration in Dbn(-/+) SMCs were normalized to WT levels by rescue expression of not only WT Drebrin but also a mutant Drebrin isoform that binds actin but fails to bind Homer.
  
  
  
  Drebrin reduces SMC activation through its interaction with the actin cytoskeleton but independently of its interaction with Homer scaffolds.
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.). stibe001@mc.duke.edu.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Stiber
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Jiao-Hui
authors.initials: JH
authors.lastname: Wu
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Igor
authors.initials: I
authors.lastname: Nepliouev
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Zhu-Shan
authors.initials: ZS
authors.lastname: Zhang
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Victoria G
authors.initials: VG
authors.lastname: Bryson
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Leigh
authors.initials: L
authors.lastname: Brian
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Rex C
authors.initials: RC
authors.lastname: Bentley
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Gordon-Weeks
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rosenberg
authors.affiliation: From the Department of Medicine, Duke University Medical Center, Durham, NC (J.A.S., J.-H.W., L.Z., I.N., Z.-S.Z., V.G.B., L.B., P.B.R., N.J.F.); Department of Pathology, Duke University Medical Center, Durham, NC (R.C.B.); and MRC Centre for Developmental Neurobiology, King's College, London, UK (P.R.G.-W.).
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Freedman
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005838:Genotype; D000072233:Homer Scaffolding Proteins / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D015398:Signal Transduction; D014162:Transfection; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: D000199:Actins; D000072233:Homer Scaffolding Proteins; D009479:Neuropeptides; D050051:Transient Receptor Potential Channels; C053386:drebrins
keywords: Drebrin; actin; homer; neointimal hyperplasia; smooth muscle