Establishment of animal models for atheroscherosis and gene therapy

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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.