Therapeutic targeting of tissue inhibitor-4 in hypertrophy and failure

心力衰竭(HF)仍然是导致发病率和死亡率的主要原因，而心力衰竭是一种 正在增加到接近流行的比例是由持续的压力超载引起的 (LVPO)。LVPO总是与细胞外基质(ECM)重塑增加有关，导致 心肌僵硬增加，舒张期功能受损，以及心衰的体征和症状。一 统一的观察是，随着LVPO和心力衰竭的进展，相对平衡发生了移动 基质金属蛋白酶(MMPs)和基质金属蛋白酶组织抑制因子(TIMPs)之间存在着相互作用。更多 具体地说，现在认识到关于TIMP表达和 功能。TIMP-4已被证明可以改变成纤维细胞的增殖、存活和胶原 表达，我们现在已经发现与TIMP-1相反，心肌水平增加 TIMP-4的表达可有效预防LVPO时ECM的异常重塑和功能障碍。这个项目 将检验心力衰竭进展与左心室肥厚是由于TIMP-4不足的中心假说 诱导，从而导致有利于成纤维细胞的TIMP化学计量平衡的改变 转化，ECM积聚，增加心肌硬度，从而驱动HF过程 往前走。这个项目有三个目标。具体目标1将建立向HF的过渡， 可以通过TIMP-1/TIMP-4平衡的变化来预测LVPO，这代表了一个临界点 由此发生成纤维细胞转化和增殖的转变，伴随着 转化生长因子(TGF)信号转导和ECM积聚，导致 局部心肌僵硬。具体目标2将证明在LVPO的渐进式模型中 在猪体内，通过一种新的水凝胶递送方式区域增强重组TIMP-4(rTIMP-4) 该系统将防止成纤维细胞转化、ECM积聚和心肌僵硬。此外， 我们将演示在开发LVPO之后rTIMP-4的本地化版本将发生逆转 这种ECM表型，从而降低心肌僵硬。在具体目标3中，我们将推进我们的 将rTIMP-4注射到冠状动脉内途径，并显示进展到 高血压性左心衰。通过一套综合的翻译研究，该项目的结果将 对TIMP(如TIMP-4)如何促进HF继发性疾病的发展提出新的见解 对于LVPO，提供了一种易于翻译的方法，其新的诊断可用于 预测这一过程的进展，并最终建立一个新的治疗方向 心力衰竭的重要原因。

Heart failure (HF) continues to be a leading cause of morbidity and mortality, and one form of HF that is increasing to near epidemic proportions is that which arises from a sustained pressure overload (LVPO). LVPO is invariably associated with increased extracellular matrix (ECM) remodeling, causing increased myocardial stiffness, impaired diastolic function, and the signs and symptoms of HF. One unifying observation is that with LVPO and the progression to HF, a shift in the relative balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) occur. More specifically, it is now recognized that a large diversity exists with respect to TIMP expression and function. TIMP-4 has been shown to alter fibroblast proliferation, survival, and collagen expression, and we have now identified that in contrast to that of TIMP-1, increased myocardial levels of TIMP-4 may actually prevent abnormal ECM remodeling and dysfunction with LVPO. This project will test the central hypothesis that HF progression with LVPO is due to inadequate TIMP-4 induction, thereby causing a shift in the TIMP stoichiometric balance favoring fibroblast transformation, ECM accumulation, increased myocardial stiffness, and thus drives the HF process forward. There are 3 aims of this project. Specific Aim 1 will establish that a transition to HF with LVPO can be predicted by a shift in TIMP-1/TIMP-4 balance and that this represents a tipping point whereby a shift in fibroblast transformation and proliferation occurs, accompanied by increased transforming growth factor (TGF) signaling and ECM accumulation, causing a rapid rise in regional myocardial stiffness. Specific Aim 2 will demonstrate that in a progressive model of LVPO in pigs, regional augmentation of recombinant TIMP-4 (rTIMP-4) through a novel hydrogel delivery system will prevent fibroblast transformation, ECM accumulation, and myocardial stiffness. Moreover, we will demonstrate that localized release of rTIMP-4 following the development of LVPO will reverse this ECM phenotype and thereby reduce myocardial stiffness. In Specific Aim 3, we will advance our delivery of rTIMP-4 to an intracoronary approach and demonstrate an interruption in the progression to HF with LVPO. Through an integrated set of translational studies, the outcomes from this project will define a new insight into how TIMPs, such as TIMP-4, contribute to the development of HF secondary to LVPO, provide a readily translatable approach in terms of a new diagnostic that can be used to predict the progression of this HF process, and finally establish a novel therapeutic direction for this significant cause of HF.