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

• 批准号: 7872344
• 负责人: Flora Sam
• 金额: $ 20.31万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872344
• 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

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）：对病理刺激的心肌肥厚是适应性不良的心脏重构的共同特征，最终导致收缩功能障碍、心力衰竭、左心室功能障碍和心肌病表型的发展。心肌细胞死亡是病理性心脏重构的一个特征，调节细胞死亡途径是预防不良心脏重构和症状性心力衰竭的一种合乎逻辑的策略。包括TGF-2蛋白超家族在内的许多细胞因子/生长因子的失调有助于左室收缩期心力衰竭的复杂发病机制。卵泡抑素家族蛋白通常通过与TGF-2超家族成员结合并修饰其功能。迄今为止，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，在卵泡抑素家族的分泌蛋白中，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著上调，而不是卵泡抑素。更重要的是，我们的试点数据还显示，与对照组相比，伴有左室收缩功能障碍（左室功能低下）的心肌病患者血清Fstl1水平升高。此外，左室功能正常化的受试者Fstl1水平降低。此外，体外试验数据还表明，Fstl1和Fstl3的作用相反：Fstl1在缺氧/再氧化的心肌细胞中保护细胞凋亡，而Fstl3促进细胞凋亡。该建议的中心假设是卵泡抑素家族的分泌蛋白Fstl1和Fstl3在心力衰竭中具有不同的模式，并参与左室收缩期心力衰竭和心脏重构的发病机制。我们将探讨循环Fstl1和Fstl3水平与心脏重构的关系。在Aim 1中，我们将检验Fstl1和Fstl3水平在左室收缩期心力衰竭患者中改变并与心脏重构相关的假设。在左室收缩功能障碍患者中，细胞因子和生长因子增加，并与病理性心脏结构重构（超声心动图）和心肌细胞重构的生物标志物（如BNP）相关。在Aim 2中，我们将检验Fstl1和Fstl3水平的变化（在基线和一年之间）与疾病进展（由超声心动图上的左室质量确定）和左室收缩期心力衰竭的BNP水平相关的假设。这项工作可能会验证心脏分泌组在心脏不良重构中的作用，并为预防或治疗左室收缩功能障碍提供新的治疗靶点。与我的同事们一起，提出的研究将有助于更好地了解心脏分泌组在病理性心脏重构中的作用及其在心衰不良心脏重构发病机制中的作用