title: Impaired glutathione redox system paradoxically suppresses angiotensin II-induced vascular remodeling.
abstract: BACKGROUND
  Angiotensin II (AII) plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH) redox status in cardiovascular remodeling remains unknown.
  
  
  METHODS
  In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute) to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU) was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs).
  
  
  RESULTS
  BSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215 ± 4 mmHg by AII at 4 weeks (p<0.01), which was not affected by BSO. Superoxide production in vascular wall was increased by AII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52 ± 0.08, 2.50 ± 0.09 and 2.10 ± 0.07 mg/g respectively, p<0.05). Surprisingly, the co-treatment of BSO totally abolished these morphological changes. Although the vascular circumferential wall stress was well compensated in AII, significantly increased in AII+BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dose-dependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester.
  
  
  CONCLUSIONS
  We demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical stress by AII.
authors.affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Izawa
authors.affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sumitomo
authors.affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakagawa
authors.affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Aizawa
authors.affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kawabe
authors.affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hasebe
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure; D019328:Buthionine Sulfoximine / Q000008:administration & dosage; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D013481:Superoxides / Q000378:metabolism; D066253:Vascular Remodeling / Q000235:genetics*
chemical_list: D013481:Superoxides; D000804:Angiotensin II; D019328:Buthionine Sulfoximine; D005978:Glutathione