Follistatin-like 1 and the cardiac secretome in human heart failure

卵泡抑素样 1 和人类心力衰竭中的心脏分泌组

基本信息

批准号：
8062288
负责人：
Flora Sam
金额：
$ 24.49万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8062288
关键词：
Apoptosis Binding Biological Markers Blood Boston Cardiac Cardiac Myocytes Cardiomyopathies Cell Death Cessation of life Clinic Complex Coronary Arteriosclerosis Data Depressed mood Development Disease Progression Echocardiography Etiology Family Follistatin Follistatin-Related Protein 1 Functional disorder Growth Factor Guidelines Heart Heart Hypertrophy Heart failure Human Hypoxia In Vitro Incidence Lead Left Left Ventricular Dysfunction Left Ventricular Function Left Ventricular Mass Medical center Mus Myocardial Ischemia Pathogenesis Pathologic Pathway interactions Patients Pattern Phenotype Play Prevention Protein Family Proteins Public Health Role Sampling Serum Stimulus Stress Systolic heart failure Testing Thick Transcript United States Ventricular Work age group cohort cytokine evidence base member new therapeutic target novel prevent programs public health relevance repository response sex

项目摘要

DESCRIPTION (provided by applicant): Cardiac hypertrophy in response to pathological stimuli represents a common feature of maladaptive cardiac remodeling, ultimately leading to the development of contractile dysfunction, heart failure, left ventricular (LV) dysfunction and a cardiomyopathic phenotype. Cardiomyocyte cell death is a feature of pathological cardiac remodeling, and modulating the cell death pathway represents a logical strategy to prevent adverse cardiac remodeling and symptomatic heart failure. Dysregulation of a number of cytokines/growth factors including the TGF-2 superfamily of proteins contributes to the complex pathogenesis of LV systolic heart failure. The follistatin family proteins generally function by binding to and modifying the members of the TGF-2 superfamily. To date, little is known about the role of follistatin-like proteins in heart failure and cardiac remodeling. Our pilot data demonstrate that among the follistatin family of secreted proteins, transcripts of follistatin-like 1 (Fstl1) and follistatin-like 3 (Fstl3), but not follistatin, are dramatically upregulated in murine hypertrophic and ischemic hearts. More importantly, our pilot data also shows increased serum Fstl1 levels in cardiomyopathy patients with LV systolic dysfunction (depressed LV function) compared to control subjects. Additionally Fstl1 levels were decreased in subjects whose LV function normalized. Furthermore in vitro pilot data also suggests opposing actions of Fstl1 and Fstl3: Fstl1 protects against apoptosis whereas Fstl3 promotes apoptosis in cardiac myocytes that have been subjected to hypoxia/reoxygenation. The central hypothesis of this proposal is that members of the follistatin family of secreted protein, Fstl1 and Fstl3, have distinct patterns in heart failure and contribute to the pathogenesis of LV systolic heart failure and cardiac remodeling. We will explore the relationship between circulating Fstl1 and Fstl3 levels and cardiac remodeling. In Aim 1 we will test the hypothesis that Fstl1 and Fstl3 levels are altered in LV systolic heart failure patients and are associated with cardiac remodeling. In patients with LV systolic dysfunction, cytokines and growth factors are increased and are associated with pathologic cardiac structural remodeling (by echocardiography) and a biomarker of cardiomyocyte remodeling (e.g., BNP). In Aim 2 we will test the hypothesis that changes in Fstl1 and Fstl3 levels (between baseline and at one year) are associated with disease progression (as determined by LV mass on echocardiography) and BNP levels in LV systolic heart failure. This work may lead to the verification of the role of the cardiac secretome in adverse cardiac remodeling, and could provide new therapeutic targets for prevention or treatment of LV systolic dysfunction. Together with my colleagues, the proposed study will lead to a better understanding of the cardiac secretome in pathological cardiac remodeling and its contribution to the pathogenesis of adverse cardiac remodeling in HF PUBLIC HEALTH RELEVANCE: Heart failure is the most significant public health problems in the world and in the United States alone, afflicts more than 5 million people and is the primary cause of 53,000 deaths annually. Despite the application of evidence-based therapies and the utilization of guidelines the incidence of HF has not declined for two decades while the mechanisms influencing the pathogenesis and progression of HF remain incompletely understood. Novel factors secreted by the heart likely plays an important pathophysiology role in how the heart itself responds to heart failure.

描述（由申请人提供）：响应病理刺激的心脏肥大代表了适应不良的心脏重塑的共同特征，最终导致收缩功能障碍，心力衰竭，左心室（LV）功能障碍和心肌病表型的发展。心肌细胞细胞死亡是病理心脏重塑的特征，调节细胞死亡途径是防止不良心脏重塑和有症状性心力衰竭的逻辑策略。许多细胞因子/生长因子的失调，包括蛋白质的TGF-2超家族，有助于LV收缩性心力衰竭的复杂发病机理。 Follistatin家族蛋白通常通过与TGF-2超家族的成员结合和修饰来发挥作用。迄今为止，对于卵泡素样蛋白在心力衰竭和心脏重塑中的作用知之甚少。我们的试验数据表明，在分泌蛋白的卵泡蛋白家族中，类似Follistatin的1（FSTL1）的转录本和类似Follistatin的3（FSTL3）（FSTL3），但不是Follistatin，在鼠肥厚和缺血性心中大大上调。更重要的是，与对照组相比，我们的试验数据还显示了LV收缩功能障碍（lv功能降低）的心肌病患者的血清FSTL1水平升高。另外，在LV功能归一化的受试者中，FSTL1水平降低。此外，体外试验数据还表明，FSTL1和FSTL3：FSTL1的相反作用可以预防凋亡，而FSTL3促进了患有低氧/氧化的心肌细胞的凋亡。该提议的中心假设是，follistatin follistatin家族FSTL1和FSTL3家族的成员在心力衰竭中具有不同的模式，并有助于LV收缩性心力衰竭和心脏重塑的发病机理。我们将探讨循环FSTL1与FSTL3水平与心脏重塑之间的关系。在AIM 1中，我们将检验以下假设：LV收缩性心力衰竭患者的FSTL1和FSTL3水平发生了改变，并且与心脏重塑有关。在LV收缩功能障碍的患者中，细胞因子和生长因子增加，并与病理心脏结构重塑（通过超声心动图）和心肌细胞重塑的生物标志物有关（例如BNP）。在AIM 2中，我们将检验以下假设：FSTL1和FSTL3水平的变化（基线和一年之间）与疾病进展（通过超声心动图上的LV质量确定）和LV收缩性心力衰竭的BNP水平有关。这项工作可能导致对心脏分泌在不良心脏重塑中的作用验证，并可能为预防或治疗LV收缩功能障碍提供新的治疗靶标。与我的同事一起，拟议的研究将使心脏重塑中心脏分型型的理解及其对HF不良心脏重塑发病机理的贡献公共卫生相关性：心力衰竭是世界上最重大的公共卫生问题，仅在美国，就会遭受超过500万人的困扰，这是每年53,000人死亡的主要原因。尽管采用了循证疗法和指南的利用，但HF的发生率尚未下降二十年，而影响HF的发病机理和进展的机制仍未完全理解。心脏分泌的新因素可能在心脏本身对心力衰竭反应的方式中起重要的病理生理作用。