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）：对病理刺激做出反应的心脏肥大是适应不良心脏重塑的一个共同特征，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性心脏重塑的一个特征，调节细胞死亡途径代表了预防不良心脏重塑和症状性心力衰竭的逻辑策略。包括 TGF-2 蛋白超家族在内的多种细胞因子/生长因子的失调导致了左心室收缩性心力衰竭的复杂发病机制。卵泡抑素家族蛋白通常通过结合并修饰 TGF-2 超家族的成员来发挥作用。迄今为止，人们对卵泡抑素样蛋白在心力衰竭和心脏重塑中的作用知之甚少。我们的初步数据表明，在分泌蛋白的卵泡抑素家族中，卵泡抑素样 1 (Fstl1) 和卵泡抑素样 3 (Fstl3) 的转录本在小鼠肥厚性和缺血性心脏中显着上调，但卵泡抑素并未显着上调。更重要的是，我们的试点数据还显示，与对照受试者相比，左心室收缩功能障碍（左心室功能低下）的心肌病患者血清 Fstl1 水平升高。此外，左心室功能正常化的受试者中 Fstl1 水平降低。此外，体外试验数据还表明 Fstl1 和 Fstl3 的相反作用：Fstl1 防止细胞凋亡，而 Fstl3 促进缺氧/复氧心肌细胞的细胞凋亡。该提议的中心假设是，分泌蛋白卵泡抑素家族的成员 Fstl1 和 Fstl3 在心力衰竭中具有不同的模式，并有助于左心室收缩性心力衰竭和心脏重塑的发病机制。我们将探讨循环 Fstl1 和 Fstl3 水平与心脏重塑之间的关系。在目标 1 中，我们将检验以下假设：Fstl1 和 Fstl3 水平在左心室收缩性心力衰竭患者中发生改变，并且与心脏重塑相关。在左心室收缩功能障碍的患者中，细胞因子和生长因子增加，并与病理性心脏结构重塑（通过超声心动图）和心肌细胞重塑的生物标志物（例如 BNP）相关。在目标 2 中，我们将检验以下假设：Fstl1 和 Fstl3 水平（基线之间和一年时）的变化与疾病进展（由超声心动图上的左室质量确定）以及左室收缩性心力衰竭中的 BNP 水平相关。这项工作可能会验证心脏分泌组在不良心脏重塑中的作用，并可能为预防或治疗左心室收缩功能障碍提供新的治疗靶点。与我的同事一起，拟议的研究将有助于更好地了解病理性心脏重塑中的心脏分泌组及其对心力衰竭不良心脏重塑发病机制的贡献公共卫生相关性：心力衰竭是世界上最严重的公共卫生问题，仅在美国，就影响着超过 500 万人，是每年 53,000 人死亡的主要原因。尽管应用了循证疗法和指南，心力衰竭的发病率二十年来并未下降，而影响心力衰竭发病机制和进展的机制仍不完全清楚。心脏分泌的新因子可能在心脏本身如何应对心力衰竭方面发挥重要的病理生理学作用。