Establishment of animal models for atheroscherosis and gene therapy

在转基因小鼠或敲除小鼠中，可以转导或删除特定基因，以研究其功能及其与人类疾病的关系。近年来，已经建立了多种转基因小鼠或基因敲除小鼠，这些小鼠过度表达或缺乏特定基因，可用于研究人类疾病的病理生理，包括动脉粥样硬化、糖尿病和高脂血症。我们建立了整合大鼠apoE基因和人脂蛋白脂肪酶基因的转基因小鼠系。apoE的过度表达降低了血浆胆固醇和甘油三酯水平，并防止饮食引起的高胆固醇血症。建立了在H2 Ld启动子控制下apoE在动脉壁过表达的转基因模型。在该模型中，脂肪条纹病变的形成被明显抑制，提示apoE具有抗动脉粥样硬化作用。为了建立新的动脉粥样硬化动物模型，将过表达脂蛋白脂肪酶的转基因小鼠与LDL受体敲除小鼠杂交。在LDL受体敲除小鼠中，脂蛋白脂肪酶的过表达显著降低血浆残馀水平，并阻止动脉粥样硬化的进展。提示通过脂蛋白脂肪酶的作用减少血浆残余物是治疗家族性高胆固醇血症等动脉粥样硬化性疾病的有效途径。最后，我们尝试了基因治疗，这将是纠正代谢性疾病中发现的遗传异常的重要治疗方法，以预防动脉粥样硬化。

In the transgenic mouse or knockout mouse, a specific gene can be transduced or deleted to study its function and relation to human diseases. Recently, various lines of transgenic mice or knockout mice which overexpress or lack a specific gene have been established and are available to study the pathophysiology of human diseases, including atherosclerosis, diabetes mellitus, and hyperlipidemia. We have established transgenic mouse lines with an integrated rat apoE gene and human lipoprotein lipase gene. Overexpression of apoE reduced plasma cholesterol and triglycerides levels, and prevented diet induced hypercholesterolemia. Another transgenc model with overexpression of apoE under control of the H2 Ld promoter in the arterial wall was established. In this model, the formation of fatty streak lesions was markedly inhibited, suggesting that apoE has anti-atherogenic actions. To establish new animal models for atherosclerosis, transgenic mice overexpressing lipoprotein lipase were crossbred with LDL receptor knockout mice. Overexpression of lipoprotein lipase markedly reduced plasma remnant levels, and prevented the progression of atherosclerosis in LDL receptor knockout mice. The results suggest that the reduction in plasma remnants through the action of lipoprotein lipase is an effective way to treat atherosclerotic disorders such as familial hypercholesterolemia. Finally, we have tried gene therapy, which will be an important therapeutic approach to correct genetic abnormalities found in metabolic diseases, for the prevention of atherosclerosis.