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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:195.)
© 2001 American Heart Association, Inc.

Vascular Biology

Superoxide Anions and Endothelial Cell Proliferation in Normoglycemia and Hyperglycemia

Michela Zanetti; Ralph M. Zwacka; John F. Engelhardt; Zvonimir S. Katusic; Timothy O’Brien

From the Endocrine Research Unit, Mayo Clinic and Foundation, Rochester, Minn (M.Z., Z.S.K., T.O.), and the Departments of Anatomy and Cell Biology, Department of Internal Medicine, University of Iowa, School of Medicine, Iowa City, Iowa (R.M.Z., J.F.E.).

Correspondence to Timothy O’Brien, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail obrien.timothy{at}mayo.edu

Abstract—Oxygen free radicals are believed to play a key role in cellular proliferation, and increased concentrations of these molecules have been implicated in the pathogenesis of endothelial dysfunction in diabetes mellitus. Our aim was to study the role of superoxide anions in endothelial cell proliferation under conditions of normoglycemia and hyperglycemia. Human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) exposed to adenoviral vectors encoding CuZnSOD (AdCuZnSOD), ß-galactosidase (Adßgal), or diluent (control) were cultured in normal glucose (NG, 5.5 mmol/L) or high glucose (HG, 28 mmol/L) medium. Cell proliferation was compared by use of [³H]thymidine incorporation and cell count in transduced and control cells in the setting of NG and HG. Transgene expression was detected in transduced cells by X-gal staining and by Western analysis and SOD activity assay in AdCuZnSOD-transduced cells. Superoxide production was significantly (P<0.05) decreased in AdCuZnSOD-transduced cells cultured in both NG and HG medium. In NG, AdCuZnSOD-transduced endothelial cells had decreased proliferation compared with control cells. After 48 hours in HG, superoxide levels were increased and DNA synthesis was decreased (P<0.05) in control and Adßgal-transduced but were not affected in AdCuZnSOD-transduced cells. In addition, after 7 days in HG, cell counts were reduced (P<0.05) in control (73±2.5%) and Adßgal-transduced (75±3.4%) but not in AdCuZnSOD-transduced cells (89±3.4%). These results suggest that either a deficiency or an excess of superoxide anions inhibits endothelial cell proliferation, and the inhibitory effect of increased superoxide due to hyperglycemia can be reversed by CuZnSOD overexpression.

Key Words: gene transfer • adenovirus • endothelium • diabetes mellitus • superoxide dismutase

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