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

Morgantini C, Imaizumi S, Grijalva V, Navab M, Fogelman AM, Reddy ST - Diabetes (2010)

Bottom Line: 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.There were no differences in glucose, insulin, total cholesterol, HDL cholesterol, and triglyceride levels between the two groups.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Pisa, Pisa, Italy.

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.

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The D-4F–treated mice demonstrated significantly decreased macrophage content. Sections from mouse aorta were analyzed by immunohistochemistry for the presence of macrophages using CD-68 antibody (as described in research design and methods). A: Representative image of macrophage content in atherosclerotic plaques. B: Quantitative analysis of macrophage content in diabetic female apoE−/− mice (diabetic) on a chow diet (n = 10) and in diabetic female apoE−/− mice treated with D-4F (diabetic/D-4F) (n = 10). ¶P < 0.01 diabetic/D-4F versus diabetic. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 2: The D-4F–treated mice demonstrated significantly decreased macrophage content. Sections from mouse aorta were analyzed by immunohistochemistry for the presence of macrophages using CD-68 antibody (as described in research design and methods). A: Representative image of macrophage content in atherosclerotic plaques. B: Quantitative analysis of macrophage content in diabetic female apoE−/− mice (diabetic) on a chow diet (n = 10) and in diabetic female apoE−/− mice treated with D-4F (diabetic/D-4F) (n = 10). ¶P < 0.01 diabetic/D-4F versus diabetic. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Quantification for macrophages in the aortic sections using CD-68 immunohistochemistry demonstrated a dramatic reduction in macrophage content in D-4F–treated diabetic apoE−/− mice when compared with untreated diabetic apoE−/− mice (78.03 ± 26.1 vs. 29.6 ± 15.2, expressed as a percentage of the whole plaque, P < 0.001) (Fig. 2A and B).


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

Morgantini C, Imaizumi S, Grijalva V, Navab M, Fogelman AM, Reddy ST - Diabetes (2010)

The D-4F–treated mice demonstrated significantly decreased macrophage content. Sections from mouse aorta were analyzed by immunohistochemistry for the presence of macrophages using CD-68 antibody (as described in research design and methods). A: Representative image of macrophage content in atherosclerotic plaques. B: Quantitative analysis of macrophage content in diabetic female apoE−/− mice (diabetic) on a chow diet (n = 10) and in diabetic female apoE−/− mice treated with D-4F (diabetic/D-4F) (n = 10). ¶P < 0.01 diabetic/D-4F versus diabetic. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992786&req=5

Figure 2: The D-4F–treated mice demonstrated significantly decreased macrophage content. Sections from mouse aorta were analyzed by immunohistochemistry for the presence of macrophages using CD-68 antibody (as described in research design and methods). A: Representative image of macrophage content in atherosclerotic plaques. B: Quantitative analysis of macrophage content in diabetic female apoE−/− mice (diabetic) on a chow diet (n = 10) and in diabetic female apoE−/− mice treated with D-4F (diabetic/D-4F) (n = 10). ¶P < 0.01 diabetic/D-4F versus diabetic. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Quantification for macrophages in the aortic sections using CD-68 immunohistochemistry demonstrated a dramatic reduction in macrophage content in D-4F–treated diabetic apoE−/− mice when compared with untreated diabetic apoE−/− mice (78.03 ± 26.1 vs. 29.6 ± 15.2, expressed as a percentage of the whole plaque, P < 0.001) (Fig. 2A and B).

Bottom Line: 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.There were no differences in glucose, insulin, total cholesterol, HDL cholesterol, and triglyceride levels between the two groups.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Pisa, Pisa, Italy.

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.

Show MeSH
Related in: MedlinePlus