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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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Decreased atherosclerotic lesion formation and lipid content in the diabetic d4F- treated mice. A: Representative images of the whole aorta by en face method in control (apoE−/− mice that were not diabetic), in diabetic apoE−/− mice (diabetic), and in diabetic apoE−/− mice treated with D-4F (diabetic/D-4F). B: Quantitative analysis of en face lesions in female apoE−/− mice on a chow diet; n = 20 for control; n = 17 for diabetic mice; and n = 17 for diabetic mice treated with D-4F (diabetic/D-4F). C: Representative sections of mouse aortic roots, stained with Oil red O. D: Quantitative analysis of lesion area in female diabetic apoE−/− mice (diabetic) and in diabetic apoE−/− mice treated with D-4F (diabetic/D-4F); n = 15 for both groups; *P < 0.01 diabetic versus control; ¶P < 0.01 diabetic versus diabetic/D-4F. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 1: Decreased atherosclerotic lesion formation and lipid content in the diabetic d4F- treated mice. A: Representative images of the whole aorta by en face method in control (apoE−/− mice that were not diabetic), in diabetic apoE−/− mice (diabetic), and in diabetic apoE−/− mice treated with D-4F (diabetic/D-4F). B: Quantitative analysis of en face lesions in female apoE−/− mice on a chow diet; n = 20 for control; n = 17 for diabetic mice; and n = 17 for diabetic mice treated with D-4F (diabetic/D-4F). C: Representative sections of mouse aortic roots, stained with Oil red O. D: Quantitative analysis of lesion area in female diabetic apoE−/− mice (diabetic) and in diabetic apoE−/− mice treated with D-4F (diabetic/D-4F); n = 15 for both groups; *P < 0.01 diabetic versus control; ¶P < 0.01 diabetic versus diabetic/D-4F. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Total atherosclerotic lesion area was quantified in control apoE−/− mice (n = 20), untreated diabetic apoE−/− mice (n = 17), and D-4F–treated diabetic apoE−/− mice (n = 17). Diabetic apoE−/− mice were found to have a 300% increase in whole aortic atherosclerotic lesion area compared with nondiabetic apoE−/− mice. Atherosclerotic lesion area was significantly reduced in D-4F–treated diabetic apoE−/− mice (0.58 ± 0.44 vs. 1.11 ± 0.73, percentage of the whole aorta, P < 0.01) (Fig. 1A and B), when compared with untreated diabetic apoE−/− mice. The average lesion area as measured by Oil-Red-O staining of the aortic sinus sections was significantly reduced in D-4F–treated diabetic apoE−/− mice when compared with untreated diabetic apoE−/− mice (36,038 ± 18,467 vs. 17,998 ± 12,491 μm2/section, P < 0.01, n = 15 per group) (Fig. 1C and D).


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)

Decreased atherosclerotic lesion formation and lipid content in the diabetic d4F- treated mice. A: Representative images of the whole aorta by en face method in control (apoE−/− mice that were not diabetic), in diabetic apoE−/− mice (diabetic), and in diabetic apoE−/− mice treated with D-4F (diabetic/D-4F). B: Quantitative analysis of en face lesions in female apoE−/− mice on a chow diet; n = 20 for control; n = 17 for diabetic mice; and n = 17 for diabetic mice treated with D-4F (diabetic/D-4F). C: Representative sections of mouse aortic roots, stained with Oil red O. D: Quantitative analysis of lesion area in female diabetic apoE−/− mice (diabetic) and in diabetic apoE−/− mice treated with D-4F (diabetic/D-4F); n = 15 for both groups; *P < 0.01 diabetic versus control; ¶P < 0.01 diabetic versus diabetic/D-4F. (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 1: Decreased atherosclerotic lesion formation and lipid content in the diabetic d4F- treated mice. A: Representative images of the whole aorta by en face method in control (apoE−/− mice that were not diabetic), in diabetic apoE−/− mice (diabetic), and in diabetic apoE−/− mice treated with D-4F (diabetic/D-4F). B: Quantitative analysis of en face lesions in female apoE−/− mice on a chow diet; n = 20 for control; n = 17 for diabetic mice; and n = 17 for diabetic mice treated with D-4F (diabetic/D-4F). C: Representative sections of mouse aortic roots, stained with Oil red O. D: Quantitative analysis of lesion area in female diabetic apoE−/− mice (diabetic) and in diabetic apoE−/− mice treated with D-4F (diabetic/D-4F); n = 15 for both groups; *P < 0.01 diabetic versus control; ¶P < 0.01 diabetic versus diabetic/D-4F. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Total atherosclerotic lesion area was quantified in control apoE−/− mice (n = 20), untreated diabetic apoE−/− mice (n = 17), and D-4F–treated diabetic apoE−/− mice (n = 17). Diabetic apoE−/− mice were found to have a 300% increase in whole aortic atherosclerotic lesion area compared with nondiabetic apoE−/− mice. Atherosclerotic lesion area was significantly reduced in D-4F–treated diabetic apoE−/− mice (0.58 ± 0.44 vs. 1.11 ± 0.73, percentage of the whole aorta, P < 0.01) (Fig. 1A and B), when compared with untreated diabetic apoE−/− mice. The average lesion area as measured by Oil-Red-O staining of the aortic sinus sections was significantly reduced in D-4F–treated diabetic apoE−/− mice when compared with untreated diabetic apoE−/− mice (36,038 ± 18,467 vs. 17,998 ± 12,491 μm2/section, P < 0.01, n = 15 per group) (Fig. 1C and D).

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