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

• DOI: 10.1124/jpet.107.119479
• Publication Date: 2007-05-09T02:43:25Z
• Authors: Stephen J. Peterson; Daniel Husney; Adam L. Kruger; Rafal Olszanecki; Francesca Ricci; Luigi F. Rodella; Alessandra Stacch...; Rita Rezzani; John A. McClung; Wilbert S. Aronow; Susumu Ikehara; Nader G. Abraham
• Keywords: Blood Glucose; Male; Nitric Oxide Synthase Type III; Kidney; Antioxidants; Diabetes Mellitus, Experimental; 03 medical and health sciences; Animals; Aorta; 0303 health sciences; Apolipoprotein A-I; Myocardium; Body Weight; diabetic rat; apolipoprotein A1; Rats; 3. Good health; Lipoproteins, LDL; Platelet Endothelial Cell Adhesion Molecule-1; Oxidative Stress; Diabetes Mellitus, Type 1; Liver; Heme Oxygenase (Decyclizing); Endothelium, Vascular; Heme Oxygenase-1; atherosclerotic lesion formation; heme oxygenase-1; density-lipoprotein; heart-disease; nitric-oxide; cells; mice; expression; D-4F; null

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 microg/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.