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

• Published in: The Journal of pharmacology and experimental therapeutics 2007-08, Vol.322 (2), p.514-520
• Main Authors: Peterson, Stephen J, Husney, Daniel, Kruger, Adam L, Olszanecki, Rafal, Ricci, Francesca, Rodella, Luigi F, Stacchiotti, Alessandra, Rezzani, Rita, McClung, John A, Aronow, Wilbert S, Ikehara, Susumu, Abraham, Nader G
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - metabolism; Aorta - enzymology; Aorta - metabolism; Apolipoprotein A-I - administration & dosage; Apolipoprotein A-I - pharmacology; Apolipoprotein A-I - therapeutic use; Blood Glucose - metabolism; Body Weight - drug effects; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - physiopathology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1 - metabolism; Kidney - enzymology; Lipoproteins, LDL - blood; Liver - enzymology; Male; Myocardium - enzymology; Nitric Oxide Synthase Type III - metabolism; Oxidative Stress - drug effects; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Rats; Rats, Sprague-Dawley; Stem Cells - metabolism; Stem Cells - pathology; Thrombomodulin - metabolism; Time Factors
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.107.119479

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.