CARDIOMYOCYTE SIGNALING BY CHOLESTEROL OZONATION PRODUCTS

胆固醇臭氧化产品的心肌细胞信号传导

• 批准号: 7381341
• 负责人: RAO M UPPU
• 金额: $ 10.74万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381341
• 关键词: CARDIOMYOCYTE; SIGNALING; CHOLESTEROL; OZONATION; PRODUCTS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary targets for reaction of ozone (O3) in the lung include all components of the epithelial lining fluid (EFL) and, to a limited extent, airway epithelial cell membranes (ECM) (32, 33). The various components that O3 can react with at the air/lung interface include unsaturated lipids, proteins, and antioxidants. The reaction of O3 with unsaturated lipids including cholesterol and cholesteryl esters occurs almost exclusively with the carbon-carbon double bonds (3, 49). This reaction produces several toxic products including Criegee ozonides, epoxides, carbonyl compounds, hydrogen peroxide, and hydroxyhydroperoxides collectively referred to as lipid ozonation products (LOPs) or, when cholesterol and its 3-acyl esters are involved, cholesterol ozonation products (COPs) . The LOPs/COPs are less reactive and more stable than O3 and, therefore, by way of diffusion or traversing through the blood, are thought to relay the toxic effects of O3 to deeper tissue strata and extra-pulmonary tissues and organs (8, 9, 15, 16, 20, 31, 35). Studies of the O3 reaction with other classes of biological target molecules in the EFL and ECM, namely, antioxidants and proteins, have identified the types of oxidative damage that can be expected when these species undergo ozonation (51 and references cited therein). However, unlike the case with lipids, these reactions have not been shown to produce mediator molecules that can relay the toxic effects of O3 to extra-pulmonary tissues and organs. This project is designed to examine the potential impact of ozonation products of cholesterol and its 3-acyl esters on cardiovascular health effects. We choose to study COPs for they seem to be one of the most likely candidates mediating the toxic effects of O3 to distant tissues and organs including the vascular system and the brain (57, 60 and the preliminary work in this proposal). We choose to study the effects of COPs on cardiomyocytes and endothelial cells because they represent two of the most important cell types of the cardiovascular system. The two specific aims of this project are: 1. To synthesize the major as well as minor products of the reaction of O3 with cholesterol, cholesteryl palmitate, and cholesteryl oleate eliciting toxicological properties. 2. To investigate the pro-oxidant effects and cell signaling components by ozonation products of cholesterol, cholesteryl palmitate, and cholesteryl oleate using cardiomyocytes and vascular endothelial cells.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。肺中臭氧反应（O3）的主要靶标包括上皮衬里液（EFL）的所有成分，并且在有限程度上是气道上皮细胞膜（ECM）（32，33）。 O3可以在空气/肺界面上反应的各种成分包括不饱和脂质，蛋白质和抗氧化剂。 O3与包括胆固醇和胆固醇酯在内的不饱和脂质的反应几乎完全与碳碳双键发生（3，49）。该反应产生了多种有毒产品，包括臭氧臭氧，环氧化物，羰基化合物，过氧化氢和羟​​基羟化氧化物，共同称为脂质臭氧化产物（LOPS），或者当胆固醇及其3-酰基酯及其3-酰基酯涉及时，胆固醇含量（Cops）。 LOP/COP的反应性较低，比O3更稳定，因此，通过扩散或通过血液遍历的方式，可以将O3的毒性带到更深的组织地层和肺部组织和器官（8、9、9、15、15、16、20、20、20、31、35）。对EFL和ECM中其他类别的生物靶标分子的O3反应的研究，即抗氧化剂和蛋白质，已经确定了当这些物种经历臭氧化时可以预期的氧化损伤类型（51和其中引用的参考文献）。但是，与脂质不同，这些反应尚未显示出可以产生可将O3毒性作用转移到肺外组织和器官的毒性作用的介体分子。 该项目旨在检查胆固醇及其3-酰基酯对心血管健康影响的潜在影响。我们选择研究警察，因为它们似乎是介导O3对远处组织和器官（包括血管系统和大脑）的毒性作用的最有可能的候选者之一（57、60以及该提案中的初步工作）。我们选择研究COP对心肌细胞和内皮细胞的影响，因为它们代表了心血管系统的两种最重要的细胞类型。该项目的两个具体目的是：1。综合O3与胆固醇，胆固醇棕榈酸酯和胆固醇Oleate诱发毒理学特性的主要和次要产物。 2。通过使用心肌细胞和血管内皮细胞的胆固醇，胆固醇棕榈酸酯和胆固醇的冰分产物研究促氧化作用和细胞信号传导成分。