Disease-specific risk factors for thrombosis following vascular interventions

摘要 血管血栓形成和止血改变与几种器官病理学有关，这种疾病- 对其中的特定介质仍知之甚少。这一点在慢性肾脏病中尤其重要。 慢性肾脏病（CKD），影响3000万美国人。CKD患者心血管疾病高发 负担，使CKD患者需要频繁的血管介入治疗，如血管内手术或 血管手术CKD环境（尿毒症）是此类治疗后血栓形成的强烈和独立的风险因素。 程序.鉴于CKD总体呈上升趋势，且介入手术频率较高， 研究这种介入后并发症和控制它们的方法是值得追求的。 CKD的特征是大量尿毒症溶质的滞留。尽管在人类和动物身上的研究 模型暗示尿毒症溶质硫酸吲哚酚和犬尿氨酸是CKD特异性风险因素， 因此，被认为是心血管疾病诱人的治疗靶点，它们的确切机制， 人们对行动仍然知之甚少。本提案将处理这一基础问题。我们搞好 近年来阐明了吲哚类尿毒症毒素的促血栓倾向，部分介导其毒性 通过上调vSMC中的组织因子。在这里，基于新的数据，我们提出了一种综合方法， 研究新发现的增加CKD血栓形成的会聚途径，包括吲哚胺2，3- 双加氧酶-1（IDO 1），犬尿氨酸生产中的关键酶，赖氨酰氧化酶（LOX），关键酶调节剂 细胞外基质重塑和血栓形成目的1研究IDO 1水平和活性的新调节 硫酸吲哚酚和/或犬尿氨酸，及其对尿毒症血栓形成的作用，使用遗传和 在CKD小鼠模型中IDO 1的药理学操作。目标2建立在我们的新发现之上， LOX表达作为硫酸吲哚酚和犬尿氨酸的靶点，从而促进尿毒症诱导的血管生成。 血栓形成这一目标采用分子和基因敲除的方法来了解LOX的控制 尿毒症环境中VSMC的生物发生及其在CKD背景下对血栓形成的作用。两个目标 研究将利用CKD小鼠的动脉和静脉血栓形成模型。成功完成本提案 将定义CKD相关的常见血栓形成介质。沿着机械的进步，我们提出的 研究可能为重新利用先进的临床化合物来管理血管疾病铺平道路。 CKD患者中的闭塞。

Abstract Vasculo-thrombosis and altered hemostasis are associated with several organ pathologies, the disease- specific mediators of which remain poorly understood. This aspect is particularly relevant in chronic kidney disease (CKD), which affects 30 million Americans. Patients with CKD suffer from high cardiovascular disease burden, making CKD patients in need of frequent vascular interventions, such as endovascular procedures or vascular surgery. A CKD milieu (uremia) is a strong and independent risk factor for thrombosis after such procedures. Given the upward trend of CKD in general, and high frequency of interventional procedures in them, investigating such post-interventional complications and means to control them is a worthy pursuit. CKD is characterized by retention of a host of uremic solutes. Although studies in humans and animal models implicate the uremic solutes indoxyl sulfate and kynurenine as CKD-specific risk factors and are, therefore, perceived as tantalizing therapeutic targets for cardiovascular disease, their exact mechanism of actions remains poorly understood. This underpinning will be addressed in the current proposal. Our work in recent years elucidated prothrombotic propensities of indolic uremic toxins, partially mediating their toxicity through upregulation of tissue factor in vSMCs. Here, building on new data, we propose an integrative approach to study newly identified converging pathways that augment thrombosis in CKD, consisting of Indoleamine 2,3- dioxygenase-1 (IDO1), a key enzyme in kynurenine production, and lysyl oxidase (LOX), a key enzyme regulator of extracellular matrix remodeling and thrombosis. Aim 1 examines a novel regulation of IDO1 level and activity by indoxyl sulfate and/or kynurenine, and its contribution to uremic thrombosis, using genetic and pharmacological manipulation of IDO1 in a CKD mouse model. Aim 2 builds on our new findings suggesting LOX expression as a target of indoxyl sulfate and kynurenine, thereby contributing to uremia-induced vasculo- thrombosis. This aim employs molecular and gene knockout approaches to understand the control of LOX biogenesis in VSMCs in a uremic milieu, and its contribution to thrombosis in context of CKD. Both aims of research will utilize arterial and venous thrombosis models in CKD mice. Successful completion of this proposal will define CKD-associated common mediators of thrombosis. Along with mechanistic advances, our proposed investigations might pave ways to repurposing advanced clinical compounds for the management of vascular occlusion in CKD patients.