Pathogenic Role of IL-18 in Sickle Cell Cardiomyopathy and Inducible Ventricular Tachycardia

IL-18 在镰状细胞心肌病和诱发性室性心动过速中的致病作用

基本信息

批准号：
9897593
负责人：
Ankit A Desai
金额：
$ 47.08万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897593
关键词：
Acute Address African American Animal Model Apoptosis Arrhythmia Binding Cardiac Cardiac development Cardiomyopathies Cardiovascular Manifestation Cell Line Cessation of life Chronic Cicatrix Coupled Data Decitabine Development Environment Exhibits Exposure to FDA approved Fibrosis Functional disorder Future Gene Expression Genetic Polymorphism Genomics Heart Heart Abnormalities Heme Hemolysis Human IL18 gene Individual Inflammasome Inflammatory Interleukin-18 Knowledge Life Expectancy Link Mediating Mediator of activation protein Mus NADPH Oxidase Outcome Pathogenicity Pathology Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Potassium Channel Pre-Clinical Model Promoter Regions Publishing Receptor Signaling Recurrence Regulation Reporting Risk Risk Factors Role Sickle Cell Sickle Cell Anemia Signal Transduction Source Sudden Death Systems Biology Testing Time Translating Treatment Efficacy Underserved Population Up-Regulation Ventricular Tachycardia clinical biomarkers cohort coronary fibrosis electrical property experience health disparity high risk hydroxyurea improved in vivo interleukin-18 receptor monocyte mouse model neutralizing antibody novel novel therapeutics personalized medicine pre-clinical premature prevent promoter sickling small molecule sudden cardiac death therapeutic target

项目摘要

ABSTRACT: Individuals with sickle cell disease exhibit cardiovascular manifestations and sudden death as the top causes of premature death. These factors, unfortunately, contribute to the plateauing of the average life expectancy of these patients (in the 4th decade) over the past two decades, yet another profound health disparity observed in African Americans (AAs). Despite expanded understanding of the defining features including systemic vaso-occlusive episodes and hemolysis, there is a paucity of information linking cardiac pathology to premature death. Using system biology approaches, we have generated highly novel information characterizing a previously unrecognized human sickle cardiomyopathy defined by myocardial fibrosis, diastolic dysfunction, prolonged repolarization, and inducible ventricular tachycardia (VT) in the “humanized” sickle mouse model. These studies further demonstrated significant upregulation of circulating IL18 gene expression, an established inflammasome and pro-fibrotic mediator upregulated by free heme, in sickle cardiomyopathy. Additionally, exposure to IL-18 was a key factor in inducing VT in sickle mice. Preliminary data further link decreased expression and activity of cardiac potassium channels (KCND2/KCND3) in sickle mice, which can prolong repolarization, to acute increases in IL-18-mediated NADPH oxidase 4 (Nox4) expression, the latter a key source of reactive oxygenation species (ROS) and induction of cardiac apoptosis. We have further shown that chronic IL-18 inhibition reduces cardiac apoptosis, fibrosis and improves diastolic function in sickle mice coupled with reduced cardiac IL-18 receptor (IL-18R) and Nox4 expression. Finally, our genomic studies have identified novel polymorphisms (SNPs) associated with enhanced IL18 expression and prolonged corrected QT (QTc) interval, an established risk factor for VT. Thus, via three specific aims (SAs), this R01 will interrogate the mechanistic basis for the hypothesis that IL-18/IL- 18R/Nox4 signaling critically downregulates KCND2 and KCND3 function acutely and promotes myocardial fibrosis with sustained activation, exacerbating sickle cardiomyopathy and VT development. SA #1 will functionally validate heme-mediated IL18 promoter regulation including SNPs in a monocyte cell line. SA #2 will define how IL-18/IL-18R/Nox4 signaling acutely downregulates KCND2/KCND3 function leading to prolonged repolarization and chronically, results in cardiac apoptosis and fibrosis. SA #3 will define the therapeutic efficacy of strategies to prevent sickle cell-associated inducible VT. The knowledge gained from this R01 will directly translate into future clinical biomarker studies evaluating risk of sudden cardiac death highlighting those patients with a higher hemolytic burden, pathogenic IL18 SNPs, and circulating IL-18 levels with theoretically higher VT risk. Additionally, the data will test for effective and novel personalized therapies in a poorly recognized and fatal manifestation of sickle cell disease.

摘要：患有镰状细胞疾病的人表现出心血管表现和猝死不幸的是，由于这些因素过早的原因，在过去的二十年中，这些患者（在第四个十年）的预期寿命，这是另一个深远的健康尽管对定义特征的了解扩大了，但在非裔美国人中观察到的差异包含系统性的血管熟悉发作和溶血，链接心脏的信息很少过早死亡的病理。心肌定义的先前未恢复的人类镰状心肌病的信息在 “人性化”小鼠模型进一步显示出循环的显着上调 IL18基因表达，一种已建立的炎性体和促纤维化介质，由自由血红素上调，在镰状心肌病。初步数据进一步链接减少心脏钾通道的表达和活性（KCND2/kCND3）在镰状小鼠中，可以延长延长的速率，以增加IL-18介导的急性增加 NADPH氧化酶4（NOX4）表达，后者是反应性氧气物种（ROS）和我们进一步表明，慢性IL-18抑制作用减少了心脏凋亡，纤维化并改善了镰状小鼠的舒张功能，以及降低心脏IL-18食谱IL-18受体（IL-18R）和 NOX4表达。最后，我们的基因组研究确定了与增强的IL18表达和延长的正确性QT（QTC）间隔是VT的确定风险因素。因此。通过三个特定目标（SAS），该R01将审问IL-18/IL-的假设的机理基础 18R/nox4信号批判性地下调kCND2和kCND3功能并促进心肌纤维化，持续激活，加剧镰状心肌病和VT开发在功能上验证了血红素介导的IL18启动子调节，其中包括单核细胞系中的SNP 将定义IL-18/IL-18R/NOX4信号传导如何急性下调KCND2/KCND3函数，导致长时间的复极和长期防止镰状细胞诱导VT的策略的治疗功效。该R01将直接转化为未来未来的临床生物标志物研究，评估某些Suddiac死亡的评估强调那些具有较高隆重负担，致病性IL18 SNP和循环IL-18水平的患者随着数据的较高的VT风险，数据将测试有效的个性化疗法镰状细胞疾病的重新认识到致命的表现。