title: Nitric oxide differentially affects proteasome activator 28 after arterial injury in type 1 and type 2 diabetic rats.
abstract: Diabetic patients display aggressive restenosis after vascular interventions, likely because of proproliferative influences of hyperglycemia and hyperinsulinemia. We have shown that nitric oxide (NO) inhibits neointimal hyperplasia in type 2, but not in type 1, diabetic rats. Here, we examined proteasome activator 28 (PA28) after arterial injury in different diabetic environments, with or without NO. We hypothesize that NO differentially affects PA28 levels based on metabolic environment.
  
  
  
  Vascular smooth muscle cell (VSMC) lysates from male, nondiabetic Lean Zucker (LZ) and Zucker Diabetic Fatty (ZDF) rats were assayed for 26S proteasome activity with or without PA28 and S-nitroso-N-acetylpenicillamine. LZ and ZDF VSMCs were treated with (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate for 24 h. Balloon-injured carotid arteries from LZ, streptozotocin-injected LZ (STZ, type 1), and ZDF (type 2) rats treated with disodium 1-[2-(carboxylato)pyrrolidin-1-iyl]diazen-1-ium-1,2-diolate were harvested at 3 or 14 d. PA28α was assessed by Western blotting and immunofluorescent staining.
  
  
  
  S-nitroso-N-acetylpenicillamine reversed PA28-stimulated increases in 26S proteasome activity in LZ and ZDF VSMCs. Increased (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate lowered PA28α in LZ VSMCs but increased PA28α in ZDF VSMCs. At 3 d after injury, disodium 1-[2-(carboxylato)pyrrolidin-1-iyl]diazen-1-ium-1,2-diolate potentiated injury-induced PA28α decreases in LZ, STZ, and ZDF rats, suggesting VSMCs, depleted at this early time point, are major sources of PA28α. At 14 d after injury, total PA28α staining returned to baseline. However, although intimal and medial PA28α staining increased in injured STZ rats, adventitial PA28α staining increased in injured ZDF rats.
  
  
  
  PA28 dysregulation may explain the differential ability of NO to inhibit neointimal hyperplasia in type 1 versus type 2 diabetes.
authors.affiliation: Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
authors.forename: Nick D
authors.initials: ND
authors.lastname: Tsihlis
authors.affiliation: Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
authors.forename: Monica P
authors.initials: MP
authors.lastname: Rodriguez
authors.affiliation: Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
authors.forename: Amanda
authors.initials: A
authors.lastname: Schwartz
authors.affiliation: Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Flynn
authors.affiliation: Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Vercammen
authors.affiliation: Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois. Electronic address: mkibbe@nmh.org.
authors.forename: Melina R
authors.initials: MR
authors.lastname: Kibbe
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020212:Carotid Artery Injuries / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000201:enzymology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000201:enzymology*; D006965:Hyperplasia / Q000209:etiology / Q000517:prevention & control; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D058426:Neointima / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C506159:PA28 protein, rat; D020011:Protective Agents; D009569:Nitric Oxide; D046988:Proteasome Endopeptidase Complex
keywords: Diabetes; Neointimal hyperplasia; Nitric oxide; Proteasome