SUPERFUND CHEMICALS AND ENDOTHELIAL CELL DYSFUNCTION

多卤代芳香烃(如多氯联苯)和多环 芳香烃(如BP)被认为与 动脉粥样硬化性疾病过程。即使这一机制 这些环境污染物的致动脉粥样硬化潜力并不是 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。血管内皮细胞“沟通” 与血液传播的细胞和裸露组织结合在一起，并充当 血浆成分的运动(例如，富含胆固醇的 脂蛋白)从血液到动脉壁。细胞损伤，或任何 破坏内皮细胞完整性从而破坏内皮细胞的事件 渗透率性质，可能参与了导致早期事件的 动脉粥样硬化病变的形成。我们建议芳香的 碳氢化合物通过导致细胞功能障碍和一种 随后内皮细胞屏障功能受到破坏。我们 假设这些事件是由1)脂类改变所调节的 2)细胞色素P-450 1A1的诱导，3) 氧化应激增加，4)DNA加合物形成和氧化 DNA损伤；5)钙代谢改变。因此， 致动脉粥样硬化脂蛋白残留物的移动范围 并进入动脉壁可能与血管病变的严重程度直接相关。 内皮细胞屏障功能紊乱。我们还假设 饮食衍生脂肪，即碳长不同的脂肪酸和 不饱和程度，可以极大地改变细胞的脂质和 氧化/抗氧化环境，从而影响芳香族 碳氢化合物介导的细胞功能障碍。此外，这项研究还 将探索某些营养素或化学物质 具有抗氧化剂或膜稳定性能，可保护 芳香烃致细胞损伤的内皮细胞。猪肉- 而人类来源的内皮细胞将被培养并用于 拟开展的研究。首先，将进行一系列研究，以 芳香烃介导血管内皮细胞作用机制的研究 细胞功能障碍。在第二阶段， 某些脂质和芳香烃对内皮细胞的影响 我们将探索新陈代谢。在第三阶段，一系列 将进行研究，以确定通过哪些机制 培养中选定的营养干预措施可能会保护激动剂细胞 在上述情况下的伤害。建议的结果 研究应确定超级基金化学中介的机制 内皮细胞功能障碍及其在动脉粥样硬化中的意义。

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.