Oxidized Lipids in Cardiovascular Disease

心血管疾病中的氧化脂质

• 批准号: 6778843
• 负责人: Nalini Santanam
• 金额: $ 35.5万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6778843
• 关键词: acyl coA; antioxidants; biological signal transduction; cardiovascular disorder; cell biology; cytotoxicity; enzyme induction /repression; fatty acids; genetically modified animals; hydrogen peroxide; intracellular; laboratory mouse; ligands; lipid metabolism; lipid transport; membrane proteins; molecular polarity; oxidative stress; oxidized lipid; peroxisome; peroxisome proliferator activated receptor; tissue /cell culture

DESCRIPTION (provided by applicant): Oxidized free fatty acids (Ox-FFA) have profound effect on cells. Most of these effects are deleterious and pro-atherogenic. Surprisingly, they also have beneficial effects such as induction of catalase. These could be some of the "hidden" effects of PPAR signaling as some of the PPAR ligands are known activators of catalase, a peroxisomal enzyme. On the other hand, the activation of antioxidant enzymes could also represent cellular defense to an oxidative stress. Understanding the basis of these effects would help us to determine conditions under which the anti-atherogenic effects would prevail over their pro- atherogenic effects. Ox-FFA are poorly transported into cells and poorly utilized for esterification reactions. Thus, small amounts of Ox-FFA that enter the cell might be more readily available for intracellular signaling pathways, i.e. as ligands for PPARs, or destined for degradation pathways. The overall hypothesis of the proposal is, "Cells regulate the uptake and presence of Ox-FFA. The small amounts of Ox-FFA that enter the cell could act as PPAR ligands. Their degradation in peroxisomes would generate H202 thus accounting for their toxicity. The induction of antioxidant enzymes by Ox-FFA might be in response to the generation of H202 or via PPARs". AIM 1: To determine why the uptake of Ox-FFA is poor as compared to that of unoxidized fatty acids. We propose that the increased polarity of Ox-FFA and/or a saturable membrane protein or domain might contribute to the poor uptake of Ox-FFA. Using chemical modifications and membrane alterations, we will determine the changes in the uptake of Ox-FFA. We will also determine the intracellular fate of Ox-FFA. AIM 2: To determine the potential degradation of Ox-FFA in the peroxisomes generating H202. We will determine the intracellular degradation of Ox-FFA such as generation of H202 and other polar products as a measure of peroxisomal oxidation. Using acyl CoA oxidase knock out mice, we will determine whether the effects of Ox-FFA could be attributed to its ability to affect peroxisomal metabolism. We will also demonstrate whether Ox-FFA, analogous to the fibrates would induce peroxisomes in animal and cell culture models. AIM 3: To determine whether cellular PPAR and non-PPAR mediated cellular responses to Ox-FFA. Using biochemical and molecular approaches, we will determine and delineate PPAR dependent and independent effects of Ox-FFA.

描述（由申请人提供）：氧化游离脂肪酸（Ox-FFA）对细胞具有深远的影响。大多数这些影响都是有害的和促动脉粥样硬化的。令人惊讶的是，它们还具有有益的作用，例如诱导过氧化氢酶。这些可能是 PPAR 信号传导的一些“隐藏”效应，因为一些 PPAR 配体是已知的过氧化氢酶（一种过氧化物酶体酶）激活剂。另一方面，抗氧化酶的激活也可能代表细胞对氧化应激的防御。了解这些作用的基础将有助于我们确定抗动脉粥样硬化作用优于促动脉粥样硬化作用的条件。 Ox-FFA 很难转运到细胞中，也很难用于酯化反应。因此，进入细胞的少量 Ox-FFA 可能更容易用于细胞内信号传导途径，即作为 PPAR 的配体，或用于降解途径。该提案的总体假设是，“细胞调节 Ox-FFA 的摄取和存在。进入细胞的少量 Ox-FFA 可以充当 PPAR 配体。它们在过氧化物酶体中的降解会产生 H2O2，从而解释其毒性。Ox-FFA 诱导抗氧化酶可能是对 H2O2 的产生或通过 PPAR 的反应”。目标 1：确定与未氧化脂肪酸相比，Ox-FFA 的吸收为何较差的原因。我们认为 Ox-FFA 和/或可饱和膜蛋白或结构域的极性增加可能导致 Ox-FFA 的摄取不良。通过化学修饰和膜改变，我们将确定 Ox-FFA 吸收的变化。我们还将确定 Ox-FFA 的细胞内命运。目的2：确定Ox-FFA在产生H 2 O 2 的过氧化物酶体中的潜在降解。我们将确定 Ox-FFA 的细胞内降解，例如 H2O2 和其他极性产物的生成，作为过氧化物酶体氧化的量度。使用酰基 CoA 氧化酶敲除小鼠，我们将确定 Ox-FFA 的作用是否可归因于其影响过氧化物酶体代谢的能力。我们还将证明类似于贝特类药物的 Ox-FFA 是否会在动物和细胞培养模型中诱导过氧化物酶体。目标 3：确定细胞 PPAR 和非 PPAR 是否介导细胞对 Ox-FFA 的反应。使用生化和分子方法，我们将确定和描述 Ox-FFA 的 PPAR 依赖性和独立作用。