Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in Apobec-1-/-/low-density lipoprotein receptor-/- mice
Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in Apobec-1-/-/low-density lipoprotein receptor-/- mice
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DOI：
10.1016/j.jacc.2007.07.081
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发表时间：
2007-12-11
影响因子：
24
通讯作者：
Fredrikson, Gunilla Nordin
中科院分区：
文献类型：
--
作者：
Schiopu, Alexandru;Frendeus, Bjoern;Fredrikson, Gunilla Nordin
目的本研究验证了一种假设，即针对特定氧化低密度脂蛋白（oxLDL）表位的人重组免疫球蛋白G1（IgG 1）抗体治疗可诱导表达载脂蛋白B-100的LDL受体缺陷小鼠现有动脉粥样硬化病变消退（apoB-100）（Apobec-1（-/-）/ LDLR-/-）。我们以前表明，对oxLDL的抗体减少小鼠动脉粥样硬化的进展。方法Apobec-1（-/-）/LDLR-/-小鼠喂高脂饮食，直到他们24周，随后被转移到食物。从25周开始，小鼠每周3次注射2种重组人IgG 1抗体（IEI-E3或2DO 3）中的任何一种，以对抗丙二酰亚胺修饰的apoB-100肽序列。在5周的时间内，转换为普通饮食导致动脉粥样硬化适度消退（8.28 +/- 4.36%; p = NS）。与对照IgG 1相比，抗体治疗诱导动脉粥样硬化进一步消退50%（2DO 3; p = 0.001）和36%（IEI-E3; p = 0.004）。2DO 3治疗也减少了斑块炎症，增强斑块的三磷酸腺苷结合盒转运体A1的表达，并抑制单核细胞趋化蛋白-1（MCP-1）在培养的monocytes.Conclusions人IgG 1对特定的oxLDL表位可以诱导动脉粥样硬化病变的快速和实质性的回归，可能是通过刺激脂质流出和抑制巨噬细胞的招聘。这些重组人抗体可能代表了一种快速消退/稳定动脉粥样硬化病变的新策略。
Objectives The present study tested the hypothesis that treatment with human recombinant immunoglobulin G1 (IgG1) antibodies against a specific oxidized low-density lipoprotein (oxLDL) epitope will induce regression of existing atherosclerotic lesions in LDL receptor-deficient mice expressing apolipoproteln B-100 (apoB-100) (Apobec-1(-/-)/ LDLR-/-).Background Oxidized LDL plays an essential role in the pathogenesis of atherosclerosis. We previously showed that an antibody against oxLDL reduces progression of atherosclerosis in mice.Methods Apobec-1(-/-)/LDLR-/- mice were fed a high-fat diet until they were 24 weeks and were subsequently transferred to chow. Starting at 25 weeks, mice were given 3 weekly injections of either of 2 recombinant human IgG1 antibodies (IEI-E3 or 2DO3) against a malondialdehyde-modified apoB-100 peptide sequence.Results At 25 weeks, atherosclerotic lesions covered 10.3 +/- 3.7% of the descending aorta. Transfer to chow diet resulted in a modest regression of atherosclerosis over a 5-week period (8.28 +/- 4.36%; p = NS). Antibody treatment induced additional regression of atherosclerosis by 50% (2DO3; p = 0.001) and 36% (IEI-E3; p = 0.004) compared with control IgG1. The 2DO3 treatment also reduced plaque inflammation, enhanced plaque expression of the adenosine triphosphate-binding cassette transporter A1, and inhibited expression of monocyte chemoattractant protein-1 in cultured monocytes.Conclusions Human IgG1 against a specific oxLDL epitope can induce rapid and substantial regression of atherosclerotic lesions, possibly by stimulating lipid efflux and inhibiting macrophage recruitment. These recombinant human antibodies could represent a novel strategy for rapid regression/stabilization of atherosclerotic lesions.