The Role of Interleukin-18 in Myocardial Hypertrophy and Failure

描述（由申请人提供）：心肌肥大及其向衰竭的过渡仍然是发病率和死亡率的重要原因。炎症细胞因子的持续产生是这一转变的所有阶段的标志。特别是白细胞介素(IL)-18在心力衰竭中表达上调，与心衰患者心肌损伤和功能障碍的严重程度及临床预后不良直接相关。我们的初步研究表明，IL-18在体外诱导心肌细胞肥大和成纤维细胞迁移和增殖，提示IL-18在体内可能具有促肥大和促纤维化的作用。我们在野生型小鼠的研究表明，横主动脉收缩（TAC）引起的压力过载导致左心室肥厚（LVH）和IL-18表达升高。值得注意的是，这种肥大可以被IL-18中和抗体显著减少。IL-18敲除小鼠对TAC的LVH显著减少；相反，在没有TAC的情况下，心脏特异性IL-18过表达可诱导LVH和心力衰竭。兔模型也表现出LVH和IL-18表达升高。此外，我们的初步人体研究清楚地证明了全身IL-18水平预测心力衰竭的预后能力。因此，我们的中心假设是IL-18是LVH的关键介质，通过诱导肥大相关激酶、胎儿基因、生长因子和基质金属蛋白酶导致病理性重塑。为了解决这一假设，我们将研究IL-18在体外心肌细胞中的依赖信号（Specific Aim 1）， IL-18介导的心脏成纤维细胞迁移和增殖的分子机制（Specific Aim 2），以及IL-18在体内LVH、纤维化和衰竭中的因果作用，使用心脏限制性IL-18KO和心脏特异性IL-18转基因小鼠（Specific Aim 3）。在小鼠中获得的结果将在压力过载肥大和失败的兔子模型中得到验证。将测量全身IL-18水平，并将其与人类心脏肥厚和衰竭的相对严重程度相关联。总的来说，这些拟议的研究将确立IL-18作为一个潜在的治疗靶点，以减轻LVH向心力衰竭的进展。

DESCRIPTION (provided by applicant): Myocardial hypertrophy and its transition to failure remains a significant cause of morbidity and mortality. Sustained production of inflammatory cytokines is a hallmark of all phases of this transition. In particular, interleukin (IL)-18 is upregulated in heart failure, which directly correlates with the severity of myocardial damage and dysfunction, and poor clinical outcome in heart failure. Our preliminary studies demonstrate that IL-18 induces cardiomyocyte hypertrophy and fibroblast migration and proliferation in vitro, suggesting potential pro-hypertrophic and pro-fibrotic roles for IL-18 in vivo. Our studies in wild-type mice show that pressure overload induced by transverse aortic constriction (TAC) leads to left ventricular hypertrophy (LVH) and increased IL-18 expression. Remarkably, this hypertrophy can be significantly reduced by IL-18 neutralizing antibodies. IL-18 knockout mice develop significantly less LVH in response to TAC; conversely, cardiac-specific overexpression of IL-18 induces LVH and heart failure in the absence of TAC. Rabbit models also exhibit LVH and increased IL-18 expression in response to TAC. Furthermore, our preliminary human studies clearly demonstrate the prognostic power of systemic IL-18 levels to predict cardiac failure. Thus, our central HYPOTHESIS is that IL-18 is a key mediator of LVH and failure that results in pathological remodeling through the induction of hypertrophy-associated kinases, fetal genes, growth factors, and matrix metalloproteinases. To address this HYPOTHESIS, we will investigate IL-18-dependent signaling in cardiomyocytes in vitro (Specific Aim 1), the molecular mechanisms involved in IL-18-mediated cardiac fibroblast migration and proliferation in vitro (Specific Aim 2), and the causal role of IL-18 in LVH, fibrosis and failure in vivo, using cardiac-restricted IL-18KO and cardiac-specific IL-18 transgenic mice (Specific Aim 3). Results obtained in mice will be validated in a rabbit model of pressure-overload hypertrophy and failure. Systemic IL-18 levels will be measured and correlated with the relative severity of cardiac hypertrophy and failure in humans. Collectively, these proposed studies will establish IL-18 as a potentially use therapeutic target to attenuate the progression of LVH to cardiac failure.