Immunization of apoE-/- mice with aldehyde-modified fibronectin inhibits the development of atherosclerosis
Immunization of apoE-/- mice with aldehyde-modified fibronectin inhibits the development of atherosclerosis
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DOI：
10.1093/cvr/cvr101
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发表时间：
2011-08-01
影响因子：
10.8
通讯作者：
Bengtsson, Eva
中科院分区：
文献类型：
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作者：
Duner, Pontus;To, Fong;Bengtsson, Eva
目的动脉壁细胞外基质中低密度脂蛋白的氧化导致丙二醛（MDA）的形成，从而修饰周围的基质蛋白。这与针对动脉粥样硬化斑块中存在的修饰的细胞外基质蛋白的免疫应答的激活有关。临床研究表明，抗MDA修饰的纤连蛋白抗体与心血管事件发生风险呈负相关。为了确定这些免疫反应在动脉粥样硬化的功能作用，我们进行了研究，其中apoE基因缺陷的小鼠免疫与MDA修饰的fibronectin.Methods和结果免疫apoE基因缺陷的小鼠与MDA修饰的纤连蛋白导致在斑块面积减少70%，剩余的斑块炎性表型较少。免疫转移到Th 2抗体反应的弱自然发生的Th 1抗体对MDA-纤连蛋白的反应。免疫小鼠脾细胞的细胞因子表达和流式细胞术分析显示调节性T细胞活化。MDA-纤连蛋白的免疫接种也被发现，以减少血浆fibronectin levels.Conclusion MDA-纤连蛋白的免疫接种显着减少apoE缺陷小鼠动脉粥样硬化的发展，这表明在人类中观察到的免疫反应可能有保护作用。MDA-纤连蛋白是动脉粥样硬化免疫调节治疗的一个可能的新靶点。
Aims Oxidation of low-density lipoprotein in the extracellular matrix of the arterial wall results in the formation of malondialdehyde (MDA) that modifies surrounding matrix proteins. This is associated with the activation of an immune response against modified extracellular matrix proteins present in atherosclerotic plaques. Clinical studies have revealed an inverse association between antibodies to MDA-modified fibronectin and risk for development of cardiovascular events. To determine the functional role of these immune responses in atherosclerosis, we performed studies in which apoE-deficient mice were immunized with MDA-modified fibronectin.Methods and results Immunization of apoE-deficient mice with MDA-modified fibronectin resulted in a 70% decrease in plaque area and a less inflammatory phenotype of remaining plaques. Immunization shifted a weak naturally occurring Th1 antibody response against MDA-fibronectin into a Th2 antibody response. Cytokine expression and flow cytometry analyses of spleen cells from immunized mice showed an activation of regulatory T cells. Immunization with MDA-fibronectin was also found to reduce plasma fibronectin levels.Conclusion Immunization with MDA-fibronectin significantly reduces the development of atherosclerosis in apoE-deficient mice suggesting that the immune response observed in humans may have a protective effect. MDA-fibronectin represents a possible novel target for immunomodulatory therapy in atherosclerosis.