Long-term treatment with the apolipoprotein A1 mimetic peptide increases antioxidants and vascular repair in type I diabetic rats.
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.
Peterson
Stephen J
SJ
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Husney
Daniel
D
Kruger
Adam L
AL
Olszanecki
Rafal
R
Ricci
Francesca
F
Rodella
Luigi F
LF
Stacchiotti
Alessandra
A
Rezzani
Rita
R
McClung
John A
JA
Aronow
Wilbert S
WS
Ikehara
Susumu
S
Abraham
Nader G
NG
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001011:Aorta / Q000201:enzymology / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000201:enzymology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D018180:Thrombomodulin / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D016632:Apolipoprotein A-I; D001786:Blood Glucose; C465468:D-4F peptide; D008077:Lipoproteins, LDL; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018180:Thrombomodulin; C099252:oxidized low density lipoprotein; D052250:Nitric Oxide Synthase Type III; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1