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转变仍然是发病率和死亡率的重要原因。炎性细胞因子的持续产生是这种转变的所有阶段的标志。特别是，白细胞介素（IL）-18在心力衰竭中上调，这与心肌损伤和功能障碍的严重程度以及心力衰竭的不良临床结果直接相关。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，表明IL-18在体内具有潜在的促肥大和促纤维化作用。我们在野生型小鼠中的研究表明，由横向主动脉缩窄（TAC）诱导的压力超负荷导致左心室肥大（LVH）和IL-18表达增加。值得注意的是，这种肥大可以通过IL-18中和抗体显著降低。IL-18基因敲除小鼠对TAC的反应明显减少了LVH;相反，在没有TAC的情况下，IL-18的心脏特异性过表达诱导LVH和心力衰竭。兔模型也表现出LVH和响应于TAC的IL-18表达增加。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和衰竭的关键介导物，其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而导致病理性重塑。为了解决这一假设，我们将在体外研究心肌细胞中IL-18依赖的信号转导（具体目标1），IL-18介导的体外心脏成纤维细胞迁移和增殖的分子机制（具体目标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-18 KO和心脏特异性IL-18转基因小鼠（具体目标3）。将在压力超负荷肥大和衰竭的兔模型中验证在小鼠中获得的结果。将测量全身IL-18水平，并将其与人类心脏肥大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作为一种潜在的治疗靶点，以减缓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.