title: Trans-cellular proliferating cell nuclear antigen gene activation in cerebral vascular smooth muscle by endothelial oxidative injury in vivo.
abstract: OBJECTIVE
  This study was undertaken to assess the role of vascular smooth muscle cell (VSMC) Ca2+ channels and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in gene regulation after oxidative endothelial injury (OEI).
  
  
  RESULTS
  OEI was produced by infusion of Na fluorescein (NaFluo) photoactivated by UV light immediately before intravenous injection. Posterior cerebral arteries were studied using immunofluorescence imaging, Western blotting, or patch clamping of isolated cells. After infusion of photoactivated NaFluo, but not NaFluo, (1) superoxide dismutase-1 (SOD-1) was upregulated in endothelium, consistent with oxidant stress; (2) the fraction of VSMC nuclei labeled for proliferating cell nuclear antigen (PCNA) increased 7-fold at 6 hours, preceded by a several-fold increase in nuclear phospho-cAMP-response element binding protein, with PCNA upregulation prevented by pretreatment with polyethylene glycol (PEG)-SOD; (3) in VSMCs, phospho-CaMKII increased 20-fold 5 minutes after OEI, with a 2-fold increase in peak Ca2+ channel currents; and (4) changes in cAMP-response element binding protein and PCNA were blocked by systemic administration of lipophilic (nifedipine) or hydrophilic (amlodipine) 1,4-dihydropyridine Ca2+ channel blockers, the calmodulin inhibitor trifluoperazine, or the CaMKII inhibitor KN-93, with none of these agents preventing SOD-1 upregulation in endothelium.
  
  
  CONCLUSIONS
  Activation of VSMC Ca2+ channels and CaMKII is a key early signaling event required for upregulation of PCNA gene expression in VSMCs after oxidative injury to endothelium.
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene St, Baltimore, Md 21201-1595, USA.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Gerzanich
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ivanova
authors.forename: Michiel S
authors.initials: MS
authors.lastname: van der Heijden
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage; D001812:Blood-Brain Barrier / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D020769:Posterior Cerebral Artery; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics*; D051381:Rats; D013449:Sulfonamides / Q000008:administration & dosage; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015533:Transcriptional Activation; D014273:Triflupromazine / Q000008:administration & dosage; D015854:Up-Regulation; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D015220:Calcium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017362:Cyclic AMP Response Element-Binding Protein; D018809:Proliferating Cell Nuclear Antigen; D013449:Sulfonamides; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014273:Triflupromazine; C072105:KN 93; D000096926:Benzenesulfonamides; C000606292:Sod1 protein, rat