Apolipoprotein A-I mimetic peptides prevent atherosclerosis development and reduce plaque inflammation in a murine model of diabetes.
OBJECTIVE
To determine the effect of the apolipoprotein A-I (ApoA-I) mimetic peptide, D-4F, on atherosclerosis development in a pre-existing diabetic condition.


METHODS
We induced hyperglycemia in 6-week-old apoE(-/-) female mice using streptozotocin. Half of the diabetic apoE(-/-) mice received D-4F in drinking water. Ten weeks later, plasma lipids, glucose, insulin levels, atherosclerotic lesions, and lesion macrophage content were measured.


RESULTS
Diabetic apoE(-/-) mice developed ∼300% more lesion area, marked dyslipidemia, increased glucose levels, and reduced plasma insulin levels when compared with nondiabetic apoE(-/-) mice. Atherosclerotic lesions were significantly reduced in the D-4F-treated diabetic apoE(-/-) mice in whole aorta (1.11 ± 0.73 vs. 0.58 ± 0.44, percentage of whole aorta, P < 0.01) and in aortic roots (36,038 ± 18,467 μm²/section vs. 17,998 ± 12,491 μm²/section, P < 0.01) when compared with diabetic apoE(-/-) mice that did not receive D-4F. Macrophage content in atherosclerotic lesions from D-4F-treated diabetic apoE(-/-) mice was significantly reduced when compared with nontreated animals (78.03 ± 26.1 vs. 29.6 ± 15.2 P < 0.001, percentage of whole plaque). There were no differences in glucose, insulin, total cholesterol, HDL cholesterol, and triglyceride levels between the two groups. Arachidonic acid, PGE₂, PGD₂, 15-HETE, 12-HETE, and 13-HODE concentrations were significantly increased in the liver tissue of diabetic apoE(-/-) mice compared with nondiabetic apoE(-/-) mice and significantly reduced by D-4F treatment.


CONCLUSIONS
Our results suggest that oral D-4F can prevent atherosclerosis development in pre-existing diabetic mice and this is associated with a reduction in hepatic arachidonic acid and oxidized fatty acid levels.
Morgantini
Cecilia
C
Department of Internal Medicine, University of Pisa, Pisa, Italy.
Imaizumi
Satoshi
S
Grijalva
Victor
V
Navab
Mohamad
M
Fogelman
Alan M
AM
Reddy
Srinivasa T
ST
D000818:Animals; D001011:Aorta / Q000473:pathology; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency*; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D048909:Diabetes Complications / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000517:prevention & control*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D058226:Plaque, Atherosclerotic / Q000473:pathology / Q000517:prevention & control*
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005230:Fatty Acids, Nonesterified; D010455:Peptides; D002784:Cholesterol
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