Rapid regression of atherosclerosis induced by liver-directed gene transfer of ApoE in ApoE-deficient mice.
Rapid regression of atherosclerosis induced by liver-directed gene transfer of ApoE in ApoE-deficient mice.
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DOI：
10.1161/01.atv.19.9.2162
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发表时间：
1999-09
期刊：
影响因子：
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通讯作者：
Kazuhisa Tsukamoto;R. Tangirala;Sam Chun;Ellen Puré;Daniel J. Rader
中科院分区：
文献类型：
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作者：
Kazuhisa Tsukamoto;R. Tangirala;Sam Chun;Ellen Puré;Daniel J. Rader
载脂蛋白E （apoE）是一种由肝脏和组织巨噬细胞合成的多功能蛋白。apoe缺陷小鼠有严重的高脂血症，并在饮食中加速动脉粥样硬化。肝源性和巨噬细胞源性apoe均可降低apoe缺乏小鼠的血浆脂蛋白水平，减缓动脉粥样硬化的进展，但在该模型中尚未证实动脉粥样硬化的消退。我们利用第二代腺病毒在已建立不同阶段动脉粥样硬化病变的鼠体内实现了人apoE的肝脏表达。正如预期的那样，人类apoE3的肝脏表达显著降低了血浆胆固醇水平。肝脏来源的apoE也在先前存在的动脉粥样硬化病变中大量积累，表明血浆apoE可以进入动脉内膜。人类apoE3在肝脏的表达持续6周，导致早期脂肪条纹病变以及主动脉根部和主动脉弓的晚期复杂病变的显著定量回归。此外，apoE的肝脏表达引起病变的实质形态学改变，包括泡沫细胞减少，平滑肌细胞和细胞外基质含量增加。同时，利用重组腺病毒也在肝脏中表达了人apoE4和apoE2。ApoE4降低胆固醇水平的程度与apoE3相同，也阻止了疾病进展，但没有引起先前存在的病变的显著消退。与apoE3和apoE4相比，ApoE2降低胆固醇水平的程度较低，并且病变进展减慢，但未诱导退化。综上所述，(1)尽管巨噬细胞来源的apoE缺失，但apoE的肝脏表达可以快速诱导apoE小鼠先前存在的动脉粥样硬化病变的消退；(2)在这种回归模型中观察到的形态学变化与其他动物模型相似，是在较长时间内引起的；(3)肝源性apoE可进入内膜动脉粥样硬化病变并被保留；(4)尽管apoE4对血浆脂蛋白的影响与apoE3相似，但其诱导回归的效果较差。apoE基因转移在apoE缺陷小鼠中诱导原有动脉粥样硬化病变快速消退，为研究与动脉粥样硬化消退相关的分子事件提供了方便的小鼠模型。
Apolipoprotein E (apoE) is a multifunctional protein synthesized by the liver and tissue macrophages. ApoE-deficient mice have severe hyperlipidemia and develop accelerated atherosclerosis on a chow diet. Both liver-derived and macrophage-derived apoEs have been shown to reduce plasma lipoprotein levels and slow the progression of atherosclerosis in apoE-deficient mice, but regression of atherosclerosis has not been demonstrated in this model. We utilized second-generation adenoviruses to achieve hepatic expression of human apoE in chow-fed, apoE-deficient mice with established atherosclerotic lesions of different stages. As expected, hepatic expression of human apoE3 significantly reduced plasma cholesterol levels. Liver-derived apoE also accumulated substantially within preexisting atherosclerotic lesions, indicating that plasma apoE gained access to the arterial intima. Hepatic expression of human apoE3 for 6 weeks resulted in significant quantitative regression of both early fatty streak lesions as well as advanced, complex lesions in both the aortic root and the aortic arch. In addition, hepatic expression of apoE induced substantial morphological changes in lesions, including decreased foam cells and increased smooth muscle cells and extracellular matrix content. In parallel, human apoE4 and apoE2 were also expressed in the liver by using recombinant adenoviruses. ApoE4 reduced cholesterol levels to the same extent as did apoE3 and also prevented progression but did not induce significant regression of preexisting lesions. ApoE2 reduced cholesterol levels to a lesser degree than did apoE3 and apoE4 and lesion progression was reduced, but regression was not induced. In summary, (1) regression of preexisting atherosclerotic lesions in apoE-deficient mice can be rapidly induced by hepatic expression of apoE, despite the absence of macrophage-derived apoE; (2) the morphological changes seen in this model of regression resemble those in other animal models, induced over longer periods of time; (3) liver-derived apoE gained access to and was retained by intimal atherosclerotic lesions; and (4) apoE4 was less effective in inducing regression, despite its effects on plasma lipoproteins that were similar to those of apoE3. The rapid regression of preexisiting atherosclerotic lesions induced by apoE gene transfer in apoE-deficient mice could provide a convenient murine model for investigation of the molecular events associated with atherosclerosis regression.