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

项目摘要/摘要 饮食和锻炼模式的改变导致了代谢综合征的大流行，这是 以内脏肥胖症、胰岛素抵抗、血脂异常为特征，且易患 动脉硬化。纤溶酶原激活物抑制物-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，能迅速抑制组织型和尿激酶型 纤溶酶原激活剂，从而稳定纤维蛋白，促进血栓形成。PAI-1也是一个重要的 胰岛素抵抗的介体和推动动脉粥样硬化发展的细胞过程，包括血管 细胞迁移和衰老。我们的团队已经证明，PAI-039，一种PAI-1的特异性抑制剂，产生 代谢小鼠模型中显著的抗动脉粥样硬化、抗肥胖和抗炎作用 综合症。这项工作首次证明了药物靶向的纤溶系统抑制 动脉粥样硬化形成。这项提案的目标是定义PAI-1 抑制剂产生这些有益的作用，并在临床相关的情况下确定其安全性和有效性 条件。假设PAI-1的药理靶向将1)抑制动脉粥样硬化的形成 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， 和胆固醇进入动脉壁，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米色脂肪细胞的形成，以及3)减轻胰岛素抵抗 代谢综合征中游离脂肪酸和胆固醇的病理性流动。一个跨学科的团队 在血管生物学、肥胖、糖脂代谢方面拥有丰富经验的研究人员，以及 已经组装了PAI-1的生物化学和药理学来开展这项工作。建议进行的研究 将涉及PAI-039和另一种新型PAI-1抑制剂CDE-268。这些化合物将在小鼠身上进行研究 利用一系列新的和复杂的方法，建立代谢综合征模型，以及在瘦小鼠身上 旨在明确PAI-1药物靶向抑制动脉粥样硬化、脂肪组织的机制 功能障碍、胰岛素抵抗和血脂异常。Ossabaw猪，一个高度翻译的模型 代谢综合征和动脉粥样硬化的形成，也将被采用，从而杠杆突出 密苏里大学环境研究人类疾病的大型动物模型。这些研究 将在临床相关条件下确定长期服用PAI-1抑制剂的有效性和安全性 条件。这一提议的中心前提是PAI-1是治疗代谢综合征的药物靶点 并降低心血管风险。这项工作具有重大的公共健康影响，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。成功完成这些任务 研究将确定PAI-1在肥胖和动脉粥样硬化中的病理作用，并将我们的团队定位为 启动代谢综合征患者PAI-1药物抑制的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.