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

描述（由申请人提供）：对病理刺激作出反应的心脏肥大代表了适应不良心脏重塑的一个共同特征，最终导致发生收缩功能障碍、心力衰竭、左心室（LV）功能障碍和心肌病表型。心肌细胞死亡是病理性心脏重构的特征，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合理策略。包括TGF-2超家族蛋白质在内的许多细胞因子/生长因子的失调导致LV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和修饰TGF-2超家族的成员来发挥功能。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。我们的试验数据表明，在卵泡抑素家族的分泌蛋白，转录卵泡抑素样1（Fstl 1）和卵泡抑素样3（Fstl 3），但不是卵泡抑素，显着上调，在鼠肥厚和缺血性心脏。更重要的是，我们的初步数据还显示，与对照受试者相比，伴有LV收缩功能障碍（LV功能低下）的心肌病患者血清Fstl 1水平升高。此外，在LV功能正常化的受试者中，Fstl 1水平降低。此外，体外试验数据还表明Fstl 1和Fstl 3的相反作用：Fstl 1保护细胞凋亡，而Fstl 3促进缺氧/复氧心肌细胞的细胞凋亡。该建议的中心假设是分泌蛋白Fstl 1和Fstl 3的卵泡抑素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制。我们将探讨循环Fstl 1和Fstl 3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：Fstl 1和Fstl 3水平在LV收缩性心力衰竭患者中改变，并且与心脏重构相关。在患有LV收缩功能障碍的患者中，细胞因子和生长因子增加，并且与病理性心脏结构重构（通过超声心动图）和心肌细胞重构的生物标志物（例如，BNP）。在目标2中，我们将检验以下假设：Fstl 1和Fstl 3水平的变化（基线和1年之间）与LV收缩性心力衰竭的疾病进展（根据超声心动图上的LV质量确定）和BNP水平相关。这项工作可能会导致心脏分泌蛋白在不利的心脏重构的作用的验证，并可能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，这项拟议的研究将导致更好地了解病理性心脏重构中的心脏分泌组及其在HF不良心脏重构发病机制中的作用 公共卫生相关性：心力衰竭是世界上最重要的公共卫生问题，仅在美国，就困扰着超过500万人，并且是每年53，000人死亡的主要原因。尽管应用循证治疗和指南的使用，HF的发病率并没有下降，而影响HF的发病机制和进展仍然不完全了解二十年。心脏分泌的新因子可能在心脏本身如何响应心力衰竭中起重要的病理生理作用。

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.