Role of Plasminogen Activator Inhibitor-1 in Adipose Tissue Dysfunction and Atherosclerosis in Metabolic Syndrome

纤溶酶原激活剂抑制剂 1 在代谢综合征脂肪组织功能障碍和动脉粥样硬化中的作用

• 批准号: 10155514
• 负责人: William P Fay
• 金额: $ 36.02万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155514
• 关键词: Address; Adipocytes; Adipose tissue; Animal Model; Animals; Antiinflammatory Effect; Aorta; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Biochemistry; Biology; Blood Vessels; Cardiovascular system; Cell Aging; Cell physiology; Central obesity; Cholesterol; Closure by clamp; Data; Development; Diabetes Mellitus; Disease; Drug Targeting; Dyslipidemias; Energy Metabolism; Environment; Exercise; Family suidae; Fibrin; Fibrinolysis; Functional disorder; Goals; Heart; Homeostasis; Human; Inflammation; Insulin Resistance; Isotopes; LDL-Receptor Related Protein 1; Lipids; Literature; Liver; Mediating; Metabolic; Metabolic dysfunction; Metabolic syndrome; Methods; Missouri; Molecular; Mus; Myocardial Infarction; Nonesterified Fatty Acids; Obesity; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Plasma; Plasma Proteins; Plasminogen Activator Inhibitor 1; Plasminogen Inactivators; Positioning Attribute; Predisposition; Property; Public Health; Research Personnel; Resistance Process; Risk; Role; Safety; Series; Serine Proteinase Inhibitors; System; Testing; Thinness; Thrombosis; Tissues; Triglycerides; Universities; Urokinase; Visceral; Weight Gain; Work; atherogenesis; base; cardiovascular risk factor; cell motility; clinical application; clinically relevant; dietary; effectiveness evaluation; experience; experimental study; fatty acid transport; glucose metabolism; high risk; human disease; human model; improved; inhibitor/antagonist; insulin mediators; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; lipid transport; macrophage; monocyte; mouse model; novel; pandemic disease; phase I trial; preservation; prevent; protein expression; small molecule; translational model; translational study; uptake; western diet

Project Summary/Abstract Changes in dietary and exercise patterns have led to a pandemic of the metabolic syndrome, which is characterized by visceral obesity, insulin resistance, dyslipidemia, and a strong predisposition to atherosclerosis. Increased expression of plasminogen activator inhibitor-1 (PAI-1) is also a hallmark of the metabolic syndrome. PAI-1 is a serine protease inhibitor that rapidly inhibits tissue- and urokinase-type plasminogen activators, thereby stabilizing fibrin and promoting thrombosis. PAI-1 is also an important mediator of insulin resistance and cellular processes that drive atherosclerosis development, including vascular cell migration and senescence. Our group has shown that PAI-039, a specific inhibitor of PAI-1, produces significant anti-atherosclerosis, anti-obesity, and anti-inflammatory effects in a murine model of the metabolic syndrome. This work is the first to demonstrate that drug targeting of the fibrinolytic system inhibits atherosclerosis formation. The objectives of this proposal are to define the mechanisms by which PAI-1 inhibitors produce these beneficial effects and determine their safety and efficacy under clinically relevant conditions. It is hypothesized that pharmacological targeting of PAI-1 will 1) inhibit atherosclerosis formation by direct vascular effects, including inhibition of macrophage invasion into plaques, vascular cell senescence, and cholesterol uptake into the arterial wall, 2) inhibit obesity by increasing energy expenditure, uncoupling protein (UCP) expression, and beige adipocyte formation in adipose tissue, and 3) attenuate insulin resistance and pathological fluxes of free fatty acids and cholesterol in the metabolic syndrome. An interdisciplinary team of investigators with extensive experience in vascular biology, obesity, glucose and lipid metabolism, and the biochemistry and pharmacology of PAI-1 has been assembled to carry out this work. The proposed studies will involve PAI-039 and another novel PAI-1 inhibitor, CDE-268. These compounds will be studied in murine models of the metabolic syndrome, as well as in lean mice, using a series of novel and sophisticated methods aimed at defining the mechanisms by which drug targeting of PAI-1 inhibits atherosclerosis, adipose tissue dysfunction, insulin resistance, and dyslipidemia. Ossabaw swine, a highly translational model of the metabolic syndrome and atherosclerosis formation, will also be employed, thus leveraging the outstanding environment at the University of Missouri for studying large animal models of human disease. These studies will determine the efficacy and safety of long-term administration of PAI-1 inhibitors under clinically relevant conditions. The central premise of this proposal is that PAI-1 is a drug target for treating metabolic syndrome and reducing cardiovascular risk. This work has major public health implications, as obesity and atherosclerosis are amongst the most important diseases facing US citizens. Successful completion of these studies will define the pathological functions of PAI-1 in obesity and atherosclerosis and position our team to initiate a phase I clinical trial of pharmacologic PAI-1 inhibition in humans with metabolic syndrome.

项目摘要/摘要 饮食和运动模式的变化导致了代谢综合征的大流行， 以内脏肥胖，胰岛素抵抗，血脂异常和强烈的易感性为特征 动脉粥样硬化。纤溶酶原激活剂1（PAI-1）的表达增加也是 代谢综合征。 PAI-1是一种丝氨酸蛋白酶抑制剂，可快速抑制组织和尿激酶类型 纤溶酶原激活剂，从而稳定纤维蛋白并促进血栓形成。 pai-1也很重要 胰岛素抵抗和细胞过程的介体，这些过程促进动脉粥样硬化的发展，包括血管 细胞迁移和衰老。我们的小组表明，PAI-039是PAI-1的特定抑制剂，会产生 在代谢的鼠模型中 综合征。这项工作是第一个证明纤维蛋白水解系统的药物靶向抑制 动脉粥样硬化形成。该提案的目标是定义PAI-1的机制 抑制剂会产生这些有益的效果，并确定其在临床相关的安全性和功效 状况。假设PAI-1的药理学靶向将抑制动脉粥样硬化的形成 通过直接血管作用，包括抑制巨噬细胞侵袭斑块，血管细胞衰老， 胆固醇吸收到动脉壁上，2）通过增加能量消耗，解偶联来抑制肥胖 蛋白质（UCP）的表达和脂肪组织中的米色脂肪细胞形成，3）减弱胰岛素抵抗 自由脂肪酸和代谢综合征中胆固醇的病理通量。一个跨学科团队 在血管生物学，肥胖，葡萄糖和脂质代谢方面具有丰富经验的研究者 PAI-1的生物化学和药理学已组装以进行这项工作。提出的研究 将涉及PAI-039和另一种新型的PAI-1抑制剂CDE-268。这些化合物将在鼠中研究 代谢综合征的模型以及瘦小鼠的模型，使用一系列新颖而复杂的方法 旨在定义靶向PAI-1的药物抑制动脉粥样硬化，脂肪组织的机制 功能障碍，胰岛素抵抗和血脂异常。 Ossabaw Swine，一种高度翻译的模型 还将采用代谢综合征和动脉粥样硬化的形成，从而利用了杰出的 密苏里大学的环境研究了大型人类疾病动物模型。这些研究 将确定在临床上相关的PAI-1抑制剂长期给药的疗效和安全性 状况。该提议的主要前提是PAI-1是治疗代谢综合征的药物靶标 并降低心血管风险。这项工作具有主要的公共卫生影响，作为肥胖和 动脉粥样硬化是美国公民面临的最重要疾病之一。这些成功完成 研究将定义PAI-1在肥胖和动脉粥样硬化中的病理功能，并将我们的团队定位为 启动对代谢综合征人类的药理学PAI-1抑制的I期临床试验。

项目成果

Elevated postischemic tissue injury and leukocyte-endothelial adhesive interactions in mice with global deficiency in caveolin-2: role of PAI-1.

Caveolin-2 全面缺乏的小鼠缺血后组织损伤和白细胞-内皮粘附相互作用升高：PAI-1 的作用。

• DOI: 10.1152/ajpheart.00682.2020
• 发表时间: 2021
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Liu,Yajun;Wang,Meifang;Wang,Derek;Fay,WilliamP;Korthuis,RonaldJ;Sowa,Grzegorz
• 通讯作者: Sowa,Grzegorz