Interleukin-18 and post infarct myocardial remodeling

描述（由申请人提供）： 摘要急性心肌梗死（MI）是美国退伍军人和平民发病率和死亡率的主要原因。已知促炎性细胞因子在MI后组织损伤、重塑和衰竭中起核心作用。白细胞介素-18（IL-18）是一种可诱导的促炎细胞因子，并通过诱导其他细胞因子、趋化因子和粘附分子来放大许多自身免疫和炎症反应。 我们的研究，无论是已发表的还是初步的，都清楚地表明IL-18参与了MI后的病理性重塑。基于这些发现，我们的中心假设是IL-18通过促进心肌细胞凋亡和肥大，通过调节细胞外基质的沉积和组成，以及通过诱导成纤维细胞增殖和纤维化，在MI后心肌重塑中起关键作用。虽然我们的长期目标是描述促炎细胞因子在心肌重塑中的确切病理作用，但我们的近期目标是确定IL-18在MI后心脏重塑和衰竭中的病因作用。为了解决我们的中心假设，提出了三个具体的目标：在具体目标1中，我们将使用野生型，心脏特异性IL-18敲除和心脏限制性过表达（IL-18转基因）小鼠来定义IL-18在梗死后心脏重塑和衰竭中的体内因果作用。 在具体目标2中，我们将描述IL-18对体外心肌细胞中细胞死亡和肥大的影响。 在具体目标3中，我们将确定IL-18依赖的分子机制，负责迁移和增殖的心脏成纤维细胞在体外。 这些新颖和创新的研究将整合功能，分子，生物化学和组织学方法，以解决中心假设。我们提出的心肌细胞和心脏成纤维细胞的体外研究将有助于通过描绘将IL-18信号传导与这种适应不良表型联系起来的分子机制来完善和进一步支持我们的体内研究。完成我们提出的研究将提供一个更好地了解心肌梗死后心肌损伤和重塑的病理生物学过程，建立IL-18作为一个致病因素，从而确定它作为一个潜在的治疗目标，在心肌梗死后心脏损伤和重塑。 公共卫生相关性： 急性心肌梗死（MI）是美国退伍军人和平民人群发病和死亡的主要原因。梗死后心肌重塑、肥大及其向充血性心力衰竭的转变是重要的疾病，在美国每年导致25万人死亡和100万人住院。了解这些病理过程的分子机制将有助于我们设计更有效的治疗策略，以更好地照顾这些患者。本研究的主要目的是更好地了解炎症细胞因子，特别是白细胞介素-18在梗死后心肌损伤、重塑和衰竭中的作用。

DESCRIPTION (provided by applicant): Abstract Acute myocardial infarction (MI) is a major cause of morbidity and mortality in the US, within both the veteran and civilian populations. Proinflammatory cytokines are known to play a central role in post-MI tissue injury, remodeling and failure. Interleukin-18 (IL-18) is an inducible proinflammatory cytokine, and amplifies many autoimmune and inflammatory responses via the induction of other cytokines, chemokines, and adhesion molecules. Our studies, both published and preliminary, clearly indicate that IL-18 participates in pathological remodeling post-MI. Based on these findings, our central hypothesis is that IL-18 plays a pivotal role in myocardial remodeling post-MI by promoting cardiomyocyte apoptosis and hypertrophy, by regulating the deposition and composition of extracellular matrix, and by inducing fibroblast proliferation and fibrosis. While our long-term objective is to delineate the precise pathological role of proinflammatory cytokines in myocardial remodeling, our immediate goal is to establish an etiological role for IL-18 in post-MI cardiac remodeling and failure. To address our central hypothesis, three specific aims are proposed: In Specific Aim 1, we will define the causal role of IL-18 in vivo in post-infarct cardiac remodeling and failure using wild-type, cardiac-specific IL-18 knockout, and cardiac-restricted overexpressor (IL-18 transgenic) mice. In Specific Aim 2, we will characterize the effects of IL-18 on cell death and hypertrophy in cardiomyocytes in vitro. In Specific Aim 3, we will identify the IL-18-dependent molecular mechanisms responsible for migration and proliferation of cardiac fibroblast in vitro. These novel and innovative studies will integrate functional, molecular, biochemical and histological approaches in order to address the central hypothesis. Our proposed in vitro studies in cardiomyocytes and cardiac fibroblasts will help refine and further support our in vivo studies by delineating the molecular mechanisms that connect IL-18 signaling to this maladaptive phenotype. Completion of our proposed studies will provide a better understanding of the pathobiological processes involved in myocardial injury and remodeling post-MI, establish IL-18 as a causative factor, and thus identify it as a potential therapeutic target in post-MI cardiac injury and remodeling. PUBLIC HEALTH RELEVANCE: Narrative Acute myocardial infarction (MI) is a major cause of morbidity and mortality in the US, within both the military veteran and civilian populations. Post-infarct myocardial remodeling, hypertrophy and its transition to congestive heart failure are important diseases, resulting in quarter million deaths and one million hospitalizations annually in the US. Understanding the molecular mechanisms underlying these pathological processes will help us design more effective therapeutic strategies to better care for these patients. The primary goal of this proposal is to better understand the role of inflammatory cytokines, interleukin-18 in particular, in post-infarct myocardial injury, remodeling and failure.