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

项目概要/摘要 饮食和运动模式的改变导致了代谢综合征的流行， 其特征在于内脏肥胖、胰岛素抵抗、血脂异常，以及 动脉粥样硬化纤溶酶原激活物抑制剂-1（派-1）表达增加也是糖尿病患者的一个标志。 代谢综合征派-1是一种丝氨酸蛋白酶抑制剂，可快速抑制组织和尿激酶型 纤溶酶原激活剂，从而稳定纤维蛋白和促进血栓形成。派-1也是重要的 胰岛素抵抗和驱动动脉粥样硬化发展的细胞过程的介质，包括血管 细胞迁移和衰老。我们的研究小组已经表明，派-039，一种派-1的特异性抑制剂， 显著的抗动脉粥样硬化、抗肥胖和抗炎作用，在代谢的鼠模型中， 综合征这项工作是第一次证明，药物靶向纤溶系统抑制 动脉粥样硬化形成。本提案的目标是确定派-1 抑制剂产生这些有益效果，并在临床相关条件下确定其安全性和有效性。 条件假设派-1的药理学靶向作用将1）抑制动脉粥样硬化形成 通过直接的血管效应，包括抑制巨噬细胞侵入斑块，血管细胞衰老， 和胆固醇摄取进入动脉壁，2）通过增加能量消耗，解偶联 蛋白（UCP）表达，和脂肪组织中米色脂肪细胞的形成，和3）减弱胰岛素抵抗 以及代谢综合征中游离脂肪酸和胆固醇的病理性流动。一支跨学门的研究团队 在血管生物学、肥胖症、糖脂代谢以及 派-1的生物化学和药理学已经组装来进行这项工作。拟议的研究 将涉及派-039和另一种新型派-1抑制剂CDE-268。这些化合物将在小鼠中进行研究。 使用一系列新颖而复杂的方法， 目的是确定药物靶向派-1抑制动脉粥样硬化、脂肪组织 功能障碍、胰岛素抵抗和血脂异常。Ossabaw猪，一种高度转化的 代谢综合征和动脉粥样硬化的形成，也将采用，从而利用突出的 在密苏里州大学的环境中研究人类疾病的大型动物模型。这些研究 将确定在临床相关条件下长期给予派-1抑制剂的疗效和安全性。 条件这一提议的中心前提是派-1是治疗代谢综合征的药物靶点 降低心血管风险。这项工作具有重大的公共卫生意义，因为肥胖和 动脉粥样硬化是美国公民面临的最重要的疾病之一。成功完成这些 研究将确定派-1在肥胖和动脉粥样硬化中的病理功能，并使我们的团队能够 在患有代谢综合征人中启动药物派-1抑制的I期临床试验。

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.