Apolipoprotein A-I mimetic peptides prevent atherosclerosis development and reduce plaque inflammation in a murine model of diabetes.

Abstract

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.

RESEARCH DESIGN AND 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.

• Authors: Cecilia Morgantini, Satoshi Imaizumi, Victor Grijalva, Mohamad Navab, Alan M Fogelman, Srinivasa T Reddy
• Journal: Diabetes (Diabetes) Vol. 59 Issue 12 Pg. 3223-8 (Dec 2010) ISSN: 1939-327X [Electronic] United States
• PMID: 20826564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apolipoprotein A-I
• Apolipoproteins E
• Cholesterol, HDL
• Cholesterol, LDL
• Fatty Acids, Nonesterified
• Peptides
• Cholesterol

Topics

• Animals
• Aorta (pathology)
• Apolipoprotein A-I (chemistry, therapeutic use)
• Apolipoproteins E (deficiency)
• Cholesterol (metabolism)
• Cholesterol, HDL (metabolism)
• Cholesterol, LDL (metabolism)
• Diabetes Complications (pathology, prevention & control)
• Disease Models, Animal
• Fatty Acids, Nonesterified (metabolism)
• Female
• Inflammation (prevention & control)
• Liver (metabolism)
• Macrophages (drug effects, pathology)
• Mice
• Peptides (pharmacology, therapeutic use)
• Plaque, Atherosclerotic (pathology, prevention & control)