title: Inhibition of apoptotic signaling and neointimal hyperplasia by tempol and nitric oxide synthase following vascular injury.
abstract: OBJECTIVE
  We hypothesized that redox-mediated apoptosis of medial smooth muscle cells (SMC) during the acute phase of vascular injury contributes to the pathophysiology of vascular disease.
  
  
  METHODS
  Apoptosis of medial SMC (1-14 days following balloon injury) was identified in rat carotid arteries by in situ DNA labeling. NADPH-derived superoxide and expression of Bcl-xL, Bax, caspase-3 and caspase-9 were assessed. The antioxidant tempol was administered in drinking water throughout the experimental period, and local adenoviral-mediated gene transfer of eNOS was performed prior to vascular injury.
  
  
  RESULTS
  Balloon injury increased NADPH-dependent superoxide production, medial SMC apoptosis, Bax-positive medial SMC index, Bax/Bcl-xL ratio, and caspase-3 and caspase-9 expression in the injured arteries. Treatment with tempol or eNOS gene transfer decreased superoxide levels and medial SMC apoptosis, with a concomitant increase in medial SMC density. Inhibition of superoxide was associated with a decreased Bax/Bcl-xL ratio, and caspase-3 and -9 expression. Tempol treatment and eNOS gene therapy significantly reduced neointima formation.
  
  
  CONCLUSIONS
  Vascular generation of reactive oxygen species participates in Bax activation and medial SMC apoptosis. These effects likely contribute to the shedding of cell-cell adhesion molecules and promote medial SMC migration and proliferation responsible for neointimal hyperplasia.
authors: Department of Anatomy and Cell Biology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors: Dammanahalli K
authors: DK
authors: Jagadeesha
authors: Francis J
authors: FJ
authors: Miller
authors: Ramesh C
authors: RC
authors: Bhalla
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000975:Antioxidants; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D003497:Cyclic N-Oxides; D013113:Spin Labels; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D013481:Superoxides; D052250:Nitric Oxide Synthase Type III; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; C001803:tempol