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CARDIOVASCULAR

Long-Term Treatment with the Apolipoprotein A1 Mimetic Peptide Increases Antioxidants and Vascular Repair in Type I Diabetic Rats

Departments of Medicine (S.J.P.), Cardiology (A.L.K., J.A.M., W.S.A.), and Pharmacology (D.H., R.O., N.G.A.), New York Medical College, Valhalla, New York; Department of Biomedical Science, University of Brescia, Italy (F.R., L.F.R., A.S., R.R.); and Kansai Medical University, Osaka, Japan (S.I.)

Apolipoprotein A1 mimetic peptide (D-4F), synthesized from D-amino acid, enhances the ability of high-density lipoprotein to protect low-density lipoprotein (LDL) against oxidation in atherosclerotic disease. Using a rat model of type I diabetes, we investigated whether chronic use of D-4F would lead to up-regulation of heme oxygenase (HO)-1, endothelial cell marker (CD31⁺), and thrombomodulin (TM) expression and increase the number of endothelial progenitor cells (EPCs). Sprague-Dawley rats were rendered diabetic with streptozotocin (STZ) and either D-4F or vehicle was administered, by i.p. injection, daily for 6 weeks (100 µg/100 g b.wt.). HO activity was measured in liver, kidney, heart, and aorta. After 6 weeks of D-4F treatment, HO activity significantly increased in the heart and aorta by 29 and 31% (p < 0.05 and p < 0.49), respectively. Long-term D-4F treatment also caused a significant increase in TM and CD31⁺ expression. D-4F administration increased antioxidant capacity, as reflected by the decrease in oxidized protein and oxidized LDL, and enhanced EPC function and/or repair, as evidenced by the increase in EPC endothelial nitric-oxide synthase (eNOS) and prevention of vascular TM and CD31⁺ loss. In conclusion, HO-1 and eNOS are relevant targets for D-4F and may contribute to the D-4F-mediated increase in TM and CD31⁺, the antioxidant and anti-inflammatory properties, and confers robust vascular protection in this animal model of type 1 diabetes.

Address correspondence to: Dr. Nader G. Abraham, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail: nader_abraham{at}nymc.edu

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