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。已知致炎细胞因子在心肌梗死后组织损伤、重塑和衰竭中发挥核心作用。白介素18(IL-18)是一种可诱导的促炎细胞因子，通过诱导其他细胞因子、趋化因子和黏附分子来放大许多自身免疫和炎症反应。我们已发表的和初步的研究清楚地表明，IL-18参与了心肌梗塞后的病理重塑。基于这些发现，我们的中心假设是，IL-18通过促进心肌细胞的凋亡和肥大，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的增殖和纤维化，在心肌梗死后的心肌重塑中发挥关键作用。虽然我们的长期目标是阐明促炎细胞因子在心肌重构中的确切病理作用，但我们的近期目标是确定IL-18在心肌梗死后心脏重构和衰竭中的病因学作用。为了解决我们的中心假设，我们提出了三个特定的目标：在特定的目标1中，我们将使用野生型、心脏特异的IL-18基因敲除和心脏限制性过表达(IL-18转基因)小鼠来确定IL-18在体内在心肌梗死后心脏重构和失败中的因果作用。在特定的目标2中，我们将研究IL-18对体外培养的心肌细胞死亡和肥大的影响。在特定的目标3中，我们将确定依赖IL-18的分子机制，在体外负责心脏成纤维细胞的迁移和增殖。这些新颖和创新的研究将整合功能、分子、生化和组织学方法，以解决中心假设。我们提议的心肌细胞和心脏成纤维细胞的体外研究将有助于完善和进一步支持我们的体内研究，因为我们描绘了将IL-18信号与这种不适应表型联系起来的分子机制。我们研究的完成将有助于更好地了解心肌梗死后心肌损伤和重构的病理生物学过程，确立IL-18为致病因子，从而确定其为心肌梗死后心脏损伤和重构的潜在治疗靶点。 公共卫生相关性： 叙事急性心肌梗死(MI)是美国退伍军人和平民中发病率和死亡率的主要原因。心肌梗死后的心肌重构、肥厚及其向充血性心力衰竭的转变是一种重要的疾病，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，以更好地照顾这些患者。这项建议的主要目标是更好地了解炎性细胞因子，特别是白细胞介素18在心肌梗死后损伤、重构和衰竭中的作用。

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.