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(Circulation. 2005;111:3126-3134.)
© 2005 American Heart Association, Inc.

Vascular Medicine

D-4F Induces Heme Oxygenase-1 and Extracellular Superoxide Dismutase, Decreases Endothelial Cell Sloughing, and Improves Vascular Reactivity in Rat Model of Diabetes

Adam L. Kruger, DO; Stephen Peterson, MD; Saadet Turkseven, PhD; Pawel M. Kaminski, PhD; Frank Fan Zhang, MD; Shuo Quan, MD, PhD; Michael S. Wolin, PhD; Nader G. Abraham, PhD

From the Departments of Medicine (A.L.K., S.P.), Pharmacology (S.T., F.F.Z., S.Q., N.G.A.), and Physiology (P.M.K., M.S.W.), New York Medical College, Valhalla, NY, and The Rockefeller University (N.G.A.), New York, NY.

Correspondence to Nader G. Abraham, PhD, Professor or Pharmacology and Medicine, New York Medical College, BSB #519, Valhalla, NY 10595. E-mail nader_abraham{at}nymc.edu

Received November 2, 2004; revision received January 28, 2005; accepted February 24, 2005.

Background— Apolipoprotein A1 mimetic peptide, synthesized from D-amino acid (D-4F), enhances the ability of HDL to protect LDL against oxidation in atherosclerotic animals.

Methods and Results— We investigated the mechanisms by which D-4F provides antioxidant effects in a diabetic model. Sprague-Dawley rats developed diabetes with administration of streptozotocin (STZ). We examined the effects of daily D-4F (100 µg/100 g of body weight, intraperitoneal injection) on superoxide (O₂^–), extracellular superoxide dismutase (EC-SOD), vascular heme oxygenase (HO-1 and HO-2) levels, and circulating endothelial cells in diabetic rats. In response to D-4F, both the quantity and activity of HO-1 were increased. O₂^– levels were elevated in diabetic rats (74.8±8x10³ cpm/10 mg protein) compared with controls (38.1±8x10³ cpm/10 mg protein; P<0.01). D-4F decreased O₂^– levels to 13.23±1x10³ (P<0.05 compared with untreated diabetics). The average number of circulating endothelial cells was higher in diabetics (50±6 cells/mL) than in controls (5±1 cells/mL) and was significantly decreased in diabetics treated with D-4F (20±3 cells/mL; P<0.005). D-4F also decreased endothelial cell fragmentation in diabetic rats. The impaired relaxation typical of blood vessels in diabetic rats was prevented by administration of D-4F (85.0±2.0% relaxation). Western blot analysis showed decreased EC-SOD in the diabetic rats, whereas D-4F restored the EC-SOD level.

Conclusions— We conclude that an increase in circulating endothelial cell sloughing, superoxide anion, and vasoconstriction in diabetic rats can be prevented by administration of D-4F, which is associated with an increase in 2 antioxidant proteins, HO-1 and EC-SOD.

Key Words: atherosclerosis • antioxidants • apolipoproteins • lipids

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