Non-pharmacological control of atherosclerosis

描述(由申请人提供)：动脉粥样硬化的炎性性质和斑块的脆弱性表明有必要确定在疾病治疗中抑制这些过程的药物。我们最近观察到，给动脉粥样硬化小鼠服用芝麻油不仅可以降低50%的血脂，而且可以预防85%以上的动脉粥样硬化。初步结果表明，芝麻油抑制了促炎基因和斑块易损性相关基因的表达，而促进了胆固醇反向转运相关基因的表达。有两种潜在的可能性-这些影响是由于芝麻油的脂肪酸成分(它含有几乎等量的单不饱和脂肪酸和多不饱和脂肪酸)的迄今未知的影响，或者是由于其不寻常的非皂化成分。这一结果也提出了一个重要的问题，降低血脂本身是否导致炎症减轻、促进斑块稳定性和增加胆固醇反向转运，或者芝麻油或其成分的基因效应是导致观察到的血脂下降和动脉粥样硬化的原因。芝麻油含有等量的单不饱和脂肪酸和多不饱和脂肪酸，并含有生物活性的非皂化成分，这些成分是有效的抗氧化剂和PPAR1激动剂。这项研究的总体目标是确定芝麻油的脂肪酸成分和非皂化成分在动脉粥样硬化中发挥有益作用的机制。不同于维生素E在预防人类动脉粥样硬化方面的失败，识别芝麻油的非皂化成分可能补充饮食不饱和脂肪的抗动脉粥样硬化作用的机制可能会导致重大的新的药理替代和方向。本研究的目的是：1.利用低密度脂蛋白受体基因敲除动物模型，比较芝麻油和葵花籽油的抗动脉粥样硬化作用，并描述和鉴定其非皂化成分的抗动脉粥样硬化作用。2.鉴定受芝麻油及其皂化和非皂化成分调控的抗动脉粥样硬化基因，并确定可能参与其作用的潜在分子机制。3.确定补充芝麻油是否会降低正常人和高危人群的心血管危险标志物。饮食预防动脉粥样硬化与药物控制相比有很大的优势，廉价、敏感和健康。这项拟议的研究可能导致确定可能是昂贵药物的“廉价”替代品的成分，为现有药物提供有价值的“辅助治疗”，它还将导致新的药物开发类别。

DESCRIPTION (provided by applicant): Inflammatory nature of atherosclerosis and the vulnerability of the plaque have suggested the need to identify agents that would inhibit these processes in the treatment of the disease. We recently observed that the administration of sesame oil to atherosclerotic mice not only reduced the blood lipids by 50% but also prevented atherosclerosis by over 85%. Preliminary results indicated that sesame oil inhibited the expression of pro-inflammatory genes and genes related to plaque vulnerability while it enhanced the expression of genes involved in reverse cholesterol transport. There are two potential possibilities-.-these effects are due hitherto unknown effects of the fatty acid constituents of sesame oil (It contains almost equal amounts of mono and polyunsaturated fatty acids), or due to its unusual non-saponifiable components. The results also posed an important question, whether lowering of plasma lipids themselves resulted in the decrease of inflammation and promoted plaque stability and increased reverse cholesterol transport or the gene effects of sesame oil or its constituents were responsible for the observed decrease in lipids and atherosclerosis. Sesame oil contains equal amounts of mono- and poly unsaturated fatty acids and contains bio-active non-saponifiable components that are potent antioxidants and PPAR1 agonists. The overall goal of the study is to determine the mechanisms by which fatty acid components and non- saponifiable components of sesame oil could exert beneficial in atherosclerosis. In lieu of vitamin E's failure in protecting human atherosclerosis, identification of the mechanisms by which the non-saponifiable components of sesame oil might complement the anti-atherosclerotic effects of dietary unsaturated fat could lead to major new pharmacological alternatives and directions. The Goals of the proposed studies are: 1. To compare the efficacy of sesame oil with sunflower oil in its anti-atherosclerotic effects with using LDL receptor knockout animals and to delineate and identify the anti-atherosclerotic effects of its non- saponifiable components. 2. Identify the anti-atherosclerotic genes that are regulated by sesame oil and its saponifiable and non- saponifiable components and to define potential molecular mechanisms that may be involved in their action. 3. To determine whether sesame oil supplementation decrease markers of cardiovascular risk in normal and high risk human subjects. Implications: Dietary prevention of atherosclerosis has major advantages to pharmacological control, being inexpensive, sensible, and healthy. The proposed study could lead to the identification of components that could be "cheap" alternatives to expensive medication offering valuable "adjunct therapy" to existing medications, It would also lead to new class of drug development.