Therapeutic targeting of tissue inhibitor-4 in hypertrophy and failure

心力衰竭（HF）仍然是发病率和死亡率的主要原因， 正在增加到接近流行病的比例，是由于持续的压力过载引起的 （LVPO）。LVPO总是与增加的细胞外基质（ECM）重塑相关， 心肌硬度增加、舒张功能受损以及HF的体征和症状。一 一致的观察结果是LVPO和进展为HF时， 基质金属蛋白酶（MMPs）和基质金属蛋白酶组织抑制剂（TIMPs）之间的相互作用。更 具体地说，现在认识到TIMP表达存在很大的多样性， 功能TIMP-4已显示改变成纤维细胞增殖、存活和胶原蛋白表达。 表达，我们现在已经确定，与TIMP-1相反，增加心肌水平， TIMP-4的表达可能实际上防止了异常ECM重塑和LVPO功能障碍。这个项目 将检验中心假设，即LVPO导致HF进展是由于TIMP-4不足 诱导，从而导致有利于成纤维细胞的TIMP化学计量平衡的转变 转化，ECM积累，增加心肌硬度，从而驱动HF过程 性新这个项目有三个目标。具体目标1将确定向HF过渡， LVPO可以通过TIMP-1/TIMP-4平衡的变化来预测，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，伴随着增加的 转化生长因子（TGF）信号传导和ECM积累，导致细胞增殖迅速增加。 局部心肌僵硬具体目标2将证明，在LVPO的进行性模型中， 在猪中，通过新型水凝胶递送局部增强重组TIMP-4（rTIMP-4） 系统将防止成纤维细胞转化、ECM积累和心肌僵硬。此外，委员会认为， 我们将证明，随着LVPO的发展，rTIMP-4的局部释放将逆转 这种ECM表型并从而降低心肌硬度。在具体目标3中，我们将推进 将rTIMP-4递送至冠状动脉内途径，并证明进展中断， HF伴LVPO。通过一套综合的转化研究，该项目的成果将 定义了一个新的见解TIMP，如TIMP-4，如何有助于HF继发性的发展， 到LVPO，提供了一种易于翻译的新诊断方法，可用于 预测这种HF过程的进展，并最终为此建立一种新的治疗方向。 HF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.