Pathophysiology of Extracellular Matrix and Desmin Breakdown in Volume Overload Heart

容量超负荷心脏中细胞外基质和结蛋白分解的病理生理学

• 批准号: 9236513
• 负责人: Louis J. Dell'Italia
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236513
• 关键词: Acute; Adrenergic Agents; Adult; Affect; American; Angiotensin II; Architecture; Autophagocytosis; Blood; Calcium; Calpain; Cardiac; Cardiac Myocytes; Caring; Cause of Death; Chymase; Collagen; Collagen Type I; Combined Modality Therapy; Complement; Complex; Coupled; Cytoskeletal Proteins; Cytoskeleton; Desmin; Development; Dictyostelium discoideum dynamin A; Digestion; Dilatation - action; Dimensions; Echocardiography; Extracellular Matrix; Extracellular Matrix Degradation; Failure; Fibroblasts; Fibronectins; Fistula; Focal Adhesions; Functional disorder; Gelatinase A; Goals; Grant; Heart; Heart Diseases; Heart failure; Homeostasis; Immunofluorescence Microscopy; Immunohistochemistry; Incidence; Intermediate Filaments; Interstitial Collagenase; Laminin; Lead; Left Ventricular Remodeling; Left atrial structure; Link; Mass Spectrum Analysis; Matrix Metalloproteinases; Measures; Mediating; Medical; Messenger RNA; Mitochondria; Mitral Valve; Mitral Valve Insufficiency; Molecular; Monitor; Morbidity - disease rate; Myocardial Contraction; Myocardium; Operative Surgical Procedures; Oxidative Stress; Patients; Phosphorylation; Postoperative Period; Principal Investigator; Process; Procollagen; Production; Protein Analysis; Proteins; Proteolysis; Rattus; Renin-Angiotensin System; Reporting; Risk; Series; Serine Protease; Source; Stress; Stretching; Structural defect; Structure; Symptoms; System; Testing; Therapeutic; Time; Tissues; Transmission Electron Microscopy; Veterans; Western Blotting; attenuation; decorin; extracellular; hemodynamics; improved; improved outcome; inhibitor/antagonist; interstitial; mortality; novel; patient population; pressure; prevent; receptor; repaired; therapeutic target; uptake

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).

细胞外基质损失在不良左心室重构中的重要性在孤立的研究中已得到充分证实。 在此，首席研究员报告了一种新描述的二尖瓣反流的纯容量超负荷。 心肌细胞细胞骨架蛋白结蛋白的分解增加了重要的细胞内结构缺陷 这种细胞外和细胞内蛋白质直接影响心肌细胞的收缩功能。 分解需要一种新的药物疗法来增强成纤维细胞细胞外基质的产生和 防止结蛋白分解，从而预防左心室扩张和心力衰竭。 建议是：1）具有高度破坏性的丝氨酸蛋白酶食糜酶通过以下途径进入心肌细胞的能力： 内吞机制，2) 心脏心肌细胞和成纤维细胞内的高食糜酶浓度，3) 食糜酶在心脏中消化结蛋白的证据，具有纯容量超负荷，4) 食糜酶的证据- 介导的细胞内自噬消化原胶原和成纤维细胞中的纤连蛋白消化形成 人们普遍认为，单纯的容量超负荷伴随着过度的容量超负荷。 为了补充食糜酶抑制剂的潜在作用，我们已经证明β1-受体。 阻断（β1-RB）可改善钙稳态和粘着斑复合物的分解。 重点关注结蛋白和细胞外基质分解是重要的体积治疗靶点 β1-RB 和 cymase 抑制联合作用可改善 LV 扩张和 在这一系列的目标中，我们将探讨细胞内（心肌细胞结蛋白）和细胞外的功能。 （成纤维细胞自噬）蛋白质分解机制及其对左室重塑和功能的影响。 VO 中细胞外基质损失和结蛋白分解的机制是多因素的，在此我们提出 针对心肌细胞的 β1-RB 和食糜酶抑制联合治疗的新机制 结蛋白分解（目标 1）和成纤维细胞通过自噬消化前胶原（目标 2），从而产生 ACF 纯 VO 中左室扩张的减弱和左室收缩功能的改善（目标 3）。