D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes.
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.


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 microg/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+/-8x10(3) cpm/10 mg protein) compared with controls (38.1+/-8x10(3) cpm/10 mg protein; P<0.01). D-4F decreased O2- levels to 13.23+/-1x10(3) (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.
Kruger
Adam L
AL
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Peterson
Stephen
S
Turkseven
Saadet
S
Kaminski
Pawel M
PM
Zhang
Frank Fan
FF
Quan
Shuo
S
Wolin
Michael S
MS
Abraham
Nader G
NG
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D016632:Apolipoprotein A-I; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000032:analysis*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000032:analysis*; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D000975:Antioxidants; D016632:Apolipoprotein A-I; C465468:D-4F peptide; D010455:Peptides; D013481:Superoxides; D013311:Streptozocin; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase