SUPERFUND CHEMICALS AND ENDOTHELIAL CELL DYSFUNCTION

SUPERFUND 化学品和内皮细胞功能障碍

• 批准号: 6217743
• 负责人: BERNHARD HENNIG
• 金额: $ 19.85万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217743
• 关键词: antiatherogenic agent; antioxidants; atherosclerosis; calcium metabolism; carbopolycyclic compound; cardiovascular disorder; cytochrome P450; cytotoxicity; environmental toxicology; halobiphenyl /halotriphenyl compound; lipid metabolism; oxidizing agents; tissue /cell culture; toxin metabolism; vascular endothelium; vascular endothelium permeability

Polyhalogenated aromatic hydrocarbons (e.g. PCBs) and polycyclic aromatic hydrocarbons (e.g., BP) have been implicated in the atherosclerotic disease process. Even though mechanisms of the atherogenic potential of these environmental contaminants are not known, critical events of cell dysfunction may occur at the endothelial cell level. The vascular endothelium 'communicates' with blood-borne cells and abluminal tissues and acts as a barrier to the movement of plasma components (e.g., cholesterol-rich lipoproteins) from the blood to the arterial wall. Cell injury, or any event which disrupts endothelial integrity and thus endothelia permeability properties, may be involved in the early events leading to atherosclerotic lesion formation. We propose that aromatic hydrocarbons are atherogenic by causing cell dysfunction and a subsequent disruption of endothelial barrier function. We hypothesize that these events are mediated by 1) alteration in lipid profile and lipid metabolism, 2) cytochrome P-450 1A1 induction, 3) increased oxidative stress, 4) DNA adduct formation and oxidative DNA damage, and 5) alteration of calcium metabolism. Thus, the extent of the movement of atherogenic lipoprotein remnants across and into the arterial wall may be directly correlated to the severity of endothelial cell barrier function disruption. We also hypothesize that diet-derived fats, i.e., fatty acids differing in carbon length and degree of unsaturation, can greatly alter the cellular lipid and oxidant/antioxidant environment and thus influence the aromatic hydrocarbon-mediated cell dysfunction. Furthermore, this research will explore mechanisms by which certain nutrients or chemicals having antioxidant or membrane stabilizing properties, may protect the endothelium from aromatic hydrocarbon-induced cell injury. Porcine- and human-derived endothelial cells will be cultured and used in the proposed research. First, a series of studies will be conducted to determine mechanisms of aromatic hydrocarbon-mediated endothelial cell dysfunction. In the second phase, the interactive events of certain lipids and aromatic hydrocarbons on endothelial cell metabolism will be explored. During the third phase, a series of studies will be undertaken to determine the mechanisms by which selected nutritional interventions in culture may protect agonist cell injury under the conditions cited above. Results of the proposed studies should identify mechanisms of Superfund Chemical-mediated endothelial cell dysfunction and their implication in atherosclerosis.

多面年芳族碳氢化合物（例如PCB）和多环芳烃 芳族烃（例如BP）与 动脉粥样硬化疾病过程。 即使 这些环境污染物的动脉粥样硬化潜力不是 已知的细胞功能障碍的关键事件可能发生在 内皮细胞水平。 血管内皮“通信” 血源性细胞和空白组织，充当 血浆成分的运动（例如，富含胆固醇 脂蛋白）从血液到动脉壁。 细胞损伤或任何 破坏内皮完整性并因此内皮的事件 渗透率属性可能参与领先的早期事件 到动脉粥样硬化病变形成。 我们提出了芳香 烃是通过引起细胞功能障碍和A 随后的内皮屏障功能的破坏。 我们 假设这些事件是由1）脂质改变介导的 剖面和脂质代谢，2）细胞色素P-450 1A1诱导，3） 增加氧化应激，4）DNA加合物形成和氧化 DNA损伤和5）钙代谢的改变。 因此， 动脉粥样硬化脂蛋白残留物的运动程度 并进入动脉壁可能与严重程度直接相关 内皮细胞屏障功能破坏。 我们还假设 饮食来源的脂肪，即脂肪酸的碳长度不同， 不饱和程度，可以极大地改变细胞脂质，并且 氧化剂/抗氧化剂环境，从而影响芳香族 碳氢化合物介导的细胞功能障碍。 此外，这项研究 将探索某些营养物质或化学物质的机制 具有抗氧化剂或膜稳定特性，可以保护 来自芳香碳诱导的细胞损伤的内皮。 por 和人类来源的内皮细胞将被培养和使用 拟议的研究。 首先，将进行一系列研究 确定芳烃介导的内皮机理 细胞功能障碍。 在第二阶段，交互事件 内皮细胞上的某些脂质和芳族烃 将探索新陈代谢。 在第三阶段，一系列 将进行研究以确定该机制 培养中选定的营养干预措施可以保护激动剂细胞 在上述条件下受伤。 提议的结果 研究应确定超级基金化学介导的机制 内皮细胞功能障碍及其对动脉粥样硬化的影响。