Conjugated linoleic acid nitration in vascular inflammation and atherosclerosis

共轭亚油酸硝化在血管炎症和动脉粥样硬化中的作用

• 批准号: 8887712
• 负责人: Luis Villacorta
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887712
• 关键词: Address; Adhesions; Agonist; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Arterial Fatty Streak; Atherosclerosis; Bioavailable; Biological Availability; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Chemotaxis; Clinical; Conjugated Linoleic Acids; Dependency; Detection; Diet; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; Endothelium; Experimental Models; Fatty Acids; Fatty acid glycerol esters; Heart; Heart Mitochondria; Human; Immune Targeting; Immune system; Inflammation Mediators; Inflammatory; Inflammatory Response; Insulin Resistance; Ischemia; LDL Cholesterol Lipoproteins; Linoleic Acids; Lipids; Mediating; Methodology; Monitor; Mus; Nitrates; Nitric Oxide; Nitrites; Nuclear Receptors; Obesity; Oils; Oral; Oral Administration; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Phenotype; Plasma; Population; Prevention; Production; Property; Public Health; Reaction; Regulation; Reporter; Research; Role; Scheme; Signal Transduction; Testing; Therapeutic; Transgenic Model; Translating; United States; Vaccines; Weight Gain; Work; adaptive immunity; arterial stiffness; attenuation; base; cellular targeting; design; diabetic; feeding; in vivo; interest; macrophage; metabolomics; mortality; mouse model; nitration; nitroalkene; novel; novel strategies; novel therapeutics; oxidized lipid; public health relevance; response; restenosis; tool; transcription factor; vascular inflammation

 DESCRIPTION (provided by applicant): Targeting vascular inflammation and the adaptive immune response is emerging as novel strategy beyond lipid lowering therapies to reduce the burden of atherosclerosis, the primary cause of mortality from cardiovascular diseases in the United States. The clinical detection and quantitation of nitric oxide-dependent fatty acid nitration products (nitroalkenes) among other fatty acids species, has sparked the interest on novel anti-inflammatory lipids targeting the immune system. Recent improvements in the methodology of detection and advances in metabolomics and lipidomics strategies have more precisely determined the abundance of the fatty acid nitration milieu. These novel tools have identified conjugated linoleic acid (CLA) as the preferential substrate for fatty acid nitration in humans. Most importantly, it has been determined that CLA nitration is readily bioavailable in humans and experimental models upon oral delivery of CLA and inorganic nitrite (NO2). However, whether parenteral nitro-CLA formation has functional benefits and salutary properties in the cardiovascular system remains to be explored. Herein, it is shown that nitro-CLA formation readily translates into anti-inflammatory mechanisms in the vasculature. In an experimental model of high-fat diet induced vascular inflammation, formation of nitro-CLA efficiently reduces arterial stiffness, a hallmark of obesity- induced vascular damage. Nitro-CLA reduces macrophage chemotaxis and adhesion to the endothelium in vivo, thus suggesting a critical role of CLA nitration in the prevention of vascular inflammatory responses. In addition, CLA nitration significantly reduces obesity-induced activation of inflammatory cells and promotes a robust anti-inflammatory phenotype switch favoring macrophage polarization towards M2 (alternative) versus M1 (classical) activation. Finally, nitro-CLA serves as an agonist of the PPARγ nuclear receptor, a key transcription factor involved in the regulation of macrophage polarization. Based on this evidence, this proposed project will test the central hypothesis that enhancing the endogenous production of nitro-conjugated linoleic acid promotes macrophage polarization towards an anti-inflammatory phenotype and protects against atherosclerosis. To address this hypothesis the following Specific Aims are proposed. Aim 1: Determine the role of nitro-CLA in macrophage anti-inflammatory properties promoting an M1 to M2 polarization. Aim 2: Define PPARγ as a key transcription factor mediating nitro-CLA anti-inflammatory mechanisms in macrophages. Aim 3: Determine that nitro-CLA-mediated macrophage PPARγ activation inhibits atherosclerosis. It is expected that with this proposal we will better define the anti-inflammatory properties of CLA nitration and establish their oral bioavailability as a novel therapeutic strategy against atherosclerosis.

 描述(申请人提供)：针对血管炎症和适应性免疫反应正在成为除降脂疗法之外的新策略，以减轻动脉粥样硬化的负担，动脉粥样硬化是美国心血管疾病死亡的主要原因。在其他脂肪酸种类中，一氧化氮依赖的脂肪酸硝化产物(硝基烯烃)的临床检测和定量引起了人们对针对免疫系统的新型抗炎脂质的兴趣。最近检测方法的改进以及代谢组学和脂类组学策略的进展更准确地确定了脂肪酸硝化环境的丰度。这些新的工具已经确定共轭亚油酸(CLA)是脂肪酸硝化的首选底物。 人类。最重要的是，已经确定CLA硝化在人体和实验模型中很容易在口服CLA和无机亚硝酸盐(NO2)后生物利用。然而，肠外硝基共轭亚油酸的形成是否在心血管系统中具有功能益处和有益特性仍有待探索。在这里，它表明，硝基共轭亚油酸的形成很容易转化为血管系统的抗炎机制。在高脂饮食诱导血管炎症的实验模型中，硝基共轭亚油酸的形成有效地降低了动脉僵硬，这是肥胖导致血管损伤的标志。在体内，硝基共轭亚油酸减少巨噬细胞的趋化作用和与内皮细胞的黏附，因此表明共轭亚油酸硝化在预防血管炎症反应中起关键作用。此外，共轭亚油酸硝化显著减少肥胖引起的炎症细胞的激活，并促进强大的抗炎表型转换，有利于巨噬细胞极化为M2(替代)而不是M1(经典)激活。最后，硝基共轭亚油酸是PPARγ核受体的激动剂，它是参与调节巨噬细胞极化的关键转录因子。基于这一证据，这项拟议的项目将检验中心假设，即增加硝基共轭亚油酸的内源性产生促进巨噬细胞向抗炎表型的极化，并保护其免受动脉粥样硬化的影响。为了解决这一假设，提出了以下具体目标。目的1：确定硝基共轭亚油酸在促进M_1~M_2极化的巨噬细胞抗炎特性中的作用。目的2：确定PPARγ是介导硝基共轭亚油酸在巨噬细胞中抗炎机制的关键转录因子。目的：确定硝基共轭亚油酸介导的巨噬细胞PPARγ活化抑制动脉粥样硬化。期望通过这项建议，我们将更好地确定共轭亚油酸硝化的抗炎特性，并确立其口服生物利用度作为一种新的抗动脉粥样硬化的治疗策略。