Non-pharmacological control of atherosclerosis

描述（由申请人提供）：动脉粥样硬化的炎症性质和斑块的脆弱性表明需要鉴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，还可以预防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与斑块脆弱性相关的基因的表达，同时增强了参与胆固醇逆向转运的基因的表达。有两种可能性。这些作用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）的迄今未知的作用，或者由于它的不寻常的不可皂化的成分。结果还提出了一个重要的问题，是否降低血脂本身导致炎症减少，促进斑块稳定性和增加胆固醇逆向转运或芝麻油或其成分的基因效应是负责观察到的脂质和动脉粥样硬化减少。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，是有效的抗氧化剂和PPAR1激动剂。 本研究的总体目标是确定芝麻油的脂肪酸成分和不可皂化成分在动脉粥样硬化中发挥有益作用的机制。代替维生素E在保护人类动脉粥样硬化方面的失败，芝麻油的非皂化成分可能补充膳食不饱和脂肪的抗动脉粥样硬化作用的机制的鉴定可能导致主要的新药理学替代品和方向。 本研究的目的是：1。使用LDL受体敲除动物比较芝麻油和向日葵油的抗动脉粥样硬化作用的有效性，并描述和鉴定其非皂化成分的抗动脉粥样硬化作用。2.确定受芝麻油及其可皂化和不可皂化组分调节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降低正常和高风险人类受试者的心血管风险标志物。 启示：动脉粥样硬化的饮食预防具有药物控制的主要优势，价格低廉，明智，健康。这项拟议的研究可能会导致识别出可能是昂贵药物的“廉价”替代品的成分，为现有药物提供有价值的“辅助治疗”，这也将导致新一类药物的开发。 公共卫生相关性：我们最近发现食用芝麻油可以抑制动脉粥样硬化。对食用芝麻油影响的基因的分析表明，芝麻油的成分抑制了动脉粥样硬化的几个方面，包括血脂，参与胆固醇转运的基因，炎症和斑块的稳定性。在拟议的研究中，我们计划确定芝麻油是否具有抗动脉粥样硬化特性的其他成分，这些成分与其脂肪酸成分不同。动脉粥样硬化的饮食预防相对于药物控制具有主要优势，且价格低廉、合理和健康。这项拟议中的研究可能会导致识别出可能是昂贵药物的“廉价”替代品的成分，并为现有药物提供有价值的“辅助治疗”，

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. PUBLIC HEALTH RELEVANCE: We recently identified that feeding sesame oil inhibited atherosclerosis. Analysis of genes affected by feeding sesame oil indicated that components of sesame oil inhibited several facets of atherosclerosis, including blood lipids, genes involved in cholesterol transport, inflammation, and the stability of the plaque. In the proposed study we plan to determine whether sesame oil possesses additional components with anti-atherosclerotic properties distinct from what could be ascribed to its fatty acid constituents. 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 and also by offering valuable "adjunct therapy" to existing medications,