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和死亡的主要原因。众所周知，促炎细胞因子在心肌梗死后组织损伤、重塑和衰竭中发挥着核心作用。白细胞介素-18 (IL-18) 是一种诱导型促炎细胞因子，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（已发表的和初步的）清楚地表明 IL-18 参与 MI 后的病理重塑。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、调节细胞外基质的沉积和组成以及诱导成纤维细胞增殖和纤维化在MI后心肌重塑中发挥关键作用。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精确病理作用，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学作用。为了解决我们的中心假设，提出了三个具体目标：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 在体内梗死后心脏重塑和衰竭中的因果作用。 在具体目标 2 中，我们将描述 IL-18 对体外心肌细胞死亡和肥大的影响。 在具体目标 3 中，我们将确定负责心脏成纤维细胞体外迁移和增殖的 IL-18 依赖性分子机制。 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体外研究将通过描述将 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帮助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有助于更好地理解 MI 后心肌损伤和重构所涉及的病理生物学过程，确定 IL-18 作为致病因素，从而将其确定为 MI 后心脏损伤和重构的潜在治疗靶点。 公共卫生相关性： 叙述 急性心肌梗塞 (MI) 是美国退伍军人和平民发病和死亡的主要原因。梗塞后心肌重塑、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。了解这些病理过程背后的分子机制将有助于我们设计更有效的治疗策略，以更好地护理这些患者。该提案的主要目标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.