4F Peptide reduces nascent atherosclerosis and induces natural antibody production in apolipoprotein E-null mice - PubMed (original) (raw)
4F Peptide reduces nascent atherosclerosis and induces natural antibody production in apolipoprotein E-null mice
Geoffrey D Wool et al. FASEB J. 2011 Jan.
Abstract
Our objective was to contrast the effect of apolipoprotein (apo) A-I mimetic peptides, such as 4F and 4F-Pro-4F (Pro), on nascent and mature atherosclerotic lesions and on levels of antibodies against oxidation-specific epitopes. Chow-fed apoE(-/-) mice were injected intraperitoneally with either the 4F peptide or a tandem helix apoA-I mimetic peptide (Pro) every other day. Mice treated with 4F, but not Pro, for 4 wk starting at 10 wk of age showed a dramatic decrease in atherosclerosis at 2 arterial sites. However, neither peptide was effective in mice treated for 8 wk starting at 20 wk of age; lesions were larger and more mature at this time point. Peptide treatment caused increased production of antibodies against oxidation-specific epitopes, including a disproportionate induction of the IgM natural antibody (NAb) E06/T15 to oxidized phospholipids. In summary, 4F, but not the tandem peptide Pro, effectively inhibited early atherogenesis but was ineffective against more mature lesions. Two different apoA-I mimetic peptides increased titers of natural antibodies against oxidation-specific epitopes.
Figures
Figure 1.
Timeline of peptide treatment. Female apoE−/− mice fed chow diet with total cholesterol between 300 to 500 mg/dl at 8 wk of age were selected for the study. Chow-fed mice were either treated for 4 wk starting at 10 wk of age or were treated for 8 wk starting at 20 wk of age.
Figure 2.
A) Total serum PON activity is not modified by peptide treatment in 8-wk study. Arylesterase specific activity of serum (micromoles phenylacetate hydrolyzed per minute per milliliter) was determined for each individual mouse. No significant differences were seen among PBS (5 mice), 4F (7 mice), or Pro treatment (7 mice). B) Total plasma SAA levels are not modified by peptide treatment in 8-wk study. Whole plasma was separated by SDS-PAGE and immunoblotted. No significant differences were seen between PBS (3 mice), 4F (3 mice), or Pro treatment (3 mice).
Figure 3.
Influence of peptides on splenic E06/T15 mRNA level. E06/T15 transcript levels were determined by real-time PCR using primers specific for the known VH CDR3 region of the E06/T15 idiotype. E06/T15 PCR signal was normalized against HPRT and expressed as levels found in peptide-treated mice relative to those found in PBS-treated control mice.
Figure 4.
A) Reduction of atherosclerotic lesion size in 4-wk protocol. Lesions were significantly reduced in the innominate artery (IA) and aortic arch (AA) in 4F-treated mice. Reduction of lesion size in the aortic root (AR) did not reach significance. B) Photomicrographs of representative lesions from the 4-wk study. Arrows indicate the small atherosclerotic lesions present at this time point.
Figure 5.
A) Lack of peptide effect in 8-wk protocol. 4F or Pro peptide did not significantly influence lesion size at any vascular site in the 8-wk protocol. B) Photomicrographs of representative lesions from the 8-wk study.
References
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