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

• 批准号: 9447193
• 负责人: Ankit A Desai
• 金额: $ 6.93万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447193
• 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

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：镰状细胞病患者表现出心血管症状和猝死 是导致过早死亡的主要原因。不幸的是，这些因素导致了平均水平的稳定 在过去的二十年里，这些患者的预期寿命（第四个十年）， 在非洲裔美国人（AAs）中观察到的差异。尽管对这些特征的理解有所扩展， 包括全身性血管闭塞发作和溶血，但缺乏与心脏疾病相关的信息。 病理学导致过早死亡使用系统生物学方法，我们已经产生了高度新颖的 描述先前未被识别的人类镰状心肌病的信息， 心脏纤维化、舒张功能障碍、复极延长和诱导性室性心动过速（VT）， “人源化”镰状小鼠模型。这些研究进一步证明了循环免疫球蛋白的显著上调。 IL 18基因表达，一种被游离血红素上调的已建立的炎性体和促纤维化介质， 镰状心肌病此外，暴露于IL-18是诱导镰状小鼠VT的关键因素。 初步数据进一步将心脏钾通道的表达和活性降低联系起来 （KCND 2/KCND 3），可以延长复极，急性增加IL-18介导的 NADPH氧化酶4（Nox 4）表达，后者是活性氧物质（ROS）的关键来源， 诱导心脏细胞凋亡。我们进一步表明，慢性IL-18抑制可减少心脏细胞凋亡， 纤维化和改善心脏舒张功能，同时降低心脏IL-18受体（IL-18 R）， Nox 4表达。最后，我们的基因组研究已经确定了新的多态性（SNPs）与 IL 18表达增强和校正QT（QTc）间期延长，这是VT的既定风险因素。因此，在本发明中， 通过三个特定的目标（SA），本R 01将询问IL-18/IL-18 18 R/Nox 4信号转导严重下调KCND 2和KCND 3的功能，并促进心肌细胞凋亡。 纤维化伴持续激活，加重镰状心肌病和VT发展。#1将 在单核细胞系中功能性验证血红素介导的IL 18启动子调控，包括SNP。SA #2 将定义IL-18/IL-18 R/Nox 4信号传导如何急剧下调KCND 2/KCND 3功能，从而导致 延长的复极化和慢性的，导致心脏细胞凋亡和纤维化。SA #3将定义 预防镰状细胞相关诱导型VT的策略的治疗效果。知识来自于 该R 01将直接转化为未来的临床生物标志物研究，以评估心源性猝死的风险 强调具有较高溶血负荷、致病性IL-18 SNP和循环IL-18水平的患者 理论上有更高的室速风险此外，这些数据将测试有效和新颖的个性化治疗， 镰状细胞病的一种不被认识的致命表现。