title: Nanoformulated copper/zinc superoxide dismutase attenuates vascular cell activation and aortic inflammation in obesity.
abstract: OBJECTIVE
  Endothelial cell (EC) oxidative stress can lead to vascular dysfunction which is an underlying event in the development of cardiovascular disease (CVD). The lack of a potent and bioavailable anti-oxidant enzyme is a major challenge in studies on antioxidant therapy. The objective of this study is to determine whether copper/zinc superoxide dismutase (CuZnSOD or SOD1) after nanoformulation (nanoSOD) can effectively reduce EC oxidative stress and/or vascular inflammation in obesity.
  
  
  METHODS
  Human aortic endothelial cells (HAECs) were treated with native- or nanoSOD for 6 h followed by treatment with linoleic acid (LA), a free fatty acid, for 6-24 h. To determine the in vivo relevance, the effectiveness of nanoSOD in reducing vascular cell activation was studied in a mouse model of diet-induced obesity.
  
  
  RESULTS
  We noted that nanoSOD was more effectively taken up by ECs than native SOD. Western blot analysis further confirmed that the intracellular accumulation of SOD1 protein was greatly increased upon nanoSOD treatment. Importantly, nanoSOD pretreatment led to a significant decrease in LA-induced oxidative stress in ECs which was associated with a marked increase in SOD enzyme activity in ECs. In vivo studies showed a significant decrease in markers of EC/vascular cell activation and/or inflammation in visceral adipose tissue (VAT), thoracic aorta, and heart collected from nanoSOD-treated mice compared to obese control mice. Interestingly, the expression of metallothionein 2, an antioxidant gene was significantly increased in nanoSOD-treated mice.
  
  
  CONCLUSIONS
  Our data show that nanoSOD is very effective in delivering active SOD to ECs and in reducing EC oxidative stress. Our data also demonstrate that nanoSOD will be a useful tool to reduce vascular cell activation in VAT and aorta in obesity which, in turn, can protect against obesity-associated CVD, in particular, hypertension.
authors.affiliation: Department of Internal Medicine/Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA; Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA. Electronic address: s.viswanathan@unmc.edu.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Saraswathi
authors.affiliation: Department of Internal Medicine/Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
authors.forename: Murali
authors.initials: M
authors.lastname: Ganesan
authors.affiliation: Department of Internal Medicine/Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Perriotte-Olson
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Devika S
authors.initials: DS
authors.lastname: Manickam
authors.affiliation: Department of Internal Medicine/Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Westwood
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Zimmerman
authors.affiliation: Radiation Science Technology Education, College of Allied Health Professions, University of Nebraska Medical Center, Omaha, USA.
authors.forename: Iman M
authors.initials: IM
authors.lastname: Ahmad
authors.affiliation: VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine/Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Cyrus V
authors.initials: CV
authors.lastname: Desouza
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
mesh_terms: D000818:Animals; D001025:Aortitis / Q000188:drug therapy* / Q000276:immunology*; D002478:Cells, Cultured; D004339:Drug Compounding; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D016166:Free Radical Scavengers / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry; D009765:Obesity / Q000188:drug therapy* / Q000276:immunology*; D013482:Superoxide Dismutase / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D016166:Free Radical Scavengers; D053769:Nanocapsules; D013482:Superoxide Dismutase
keywords: Free fatty acid; NanoSOD; Obesity; Oxidative stress; Superoxide dismutase; Vascular inflammation