Pathophysiology of Extracellular Matrix and Desmin Breakdown in Volume Overload Heart

细胞外基质丢失在左室重构不良中的重要性在孤立性心肌梗死中已得到充分证实。 二尖瓣返流的纯容量超负荷。在这里，主要研究者报告了一种新描述的 心肌细胞骨架蛋白结蛋白的分解增加了一个重要的细胞内结构缺陷 直接影响心肌细胞的收缩功能。这种细胞外和细胞内的蛋白质 分解要求一种新的医学疗法，其增强成纤维细胞外基质的产生， 防止结蛋白分解，以防止LV扩张和心力衰竭。当前的新发现 建议是：1）高度破坏性的丝氨酸蛋白酶糜酶通过一种蛋白酶进入心肌细胞的能力， 内吞机制，2）心脏中心肌细胞和成纤维细胞内的高糜酶浓度，3） 在心脏中糜酶消化结蛋白的证据，具有纯容量超负荷，4）糜酶- 原胶原介导的细胞内自噬消化和成纤维细胞中的纤连蛋白消化形成了 心脏容量超负荷人们普遍认为，纯粹的容量超负荷伴随着过度的 肾上腺素能冲动为了补充糜酶抑制剂的潜在作用，我们已经证明β1-受体 阻断剂（β1-RB）可改善钙稳态和粘着斑复合物的分解。我们 假设结蛋白和细胞外基质分解是重要治疗靶点， 对β1-RB和糜酶联合抑制有反应的超负荷，可改善LV扩张， 功能在一系列的目标中，我们将探讨细胞内（心肌细胞结蛋白）和细胞外 （成纤维细胞自噬）蛋白质分解的机制以及对LV重塑和功能的结果影响。 VO中细胞外基质丢失和结蛋白破坏的机制是多因素的，在此我们提出 靶向心肌细胞的β1-RB和糜酶抑制剂联合治疗的新机制 结蛋白分解（Aim 1）和成纤维细胞通过自噬消化前胶原（Aim 2），导致 ACF的纯VO中LV扩张的衰减和LV收缩功能的改善（目的3）。

The importance of the extracellular matrix loss in adverse LV remodeling is well established in the isolated pure volume overload of mitral regurgitation. Here the Principal Investigator reports a newly described breakdown of cardiomyocyte cytoskeletal protein desmin that adds an important intracellular structural defect with a direct impact on cardiomyocyte contractile function. This extracellular and intracellular protein breakdown mandates a novel medical therapy that enhances fibroblast extracellular matrix production and prevents desmin breakdown in order to prevent LV dilatation and heart failure. The novel findings of the current proposal are: 1) the ability of the highly destructive serine protease chymase to enter the cardiomyocyte via an endocytic mechanism, 2) the high chymase concentration within cardiomyocytes and fibroblasts in the heart, 3) evidence of chymase digestion of desmin in the heart with a pure volume overload, 4) evidence of chymase- mediated intracellular autophagic digestion of procollagen and fibronectin digestion in fibroblasts form the volume overloaded heart. It is well accepted that a pure volume overload is accompanied by excessive adrenergic drive. To complement the potential actions of chymase inhibitor, we have shown that β1-receptor blockade (β1-RB) improves calcium homeostasis and breakdown of the focal adhesion complex. We hypothesize that desmin and extracellular matrix breakdown are important therapeutic targets in volume overload that are responsive to a combined β1-RB and chymase inhibition that improves LV dilatation and function. In the series of aims, we will explore the intracellular (cardiomyocyte desmin) and extracellular (fibroblast autophagy) mechanisms of protein breakdown and resultant effects on LV remodeling and function. The mechanism of extracellular matrix loss and desmin breakdown in VO is multifactorial and here we propose novel mechanisms for a combined therapy of β1-RB and chymase inhibition that will target cardiomyocyte desmin breakdown (Aim 1) and fibroblast digestion of procollagen by autophagy (Aim 2), resulting in attenuation of LV dilatation and improvement in LV systolic function in the pure VO of ACF (Aim 3).