AGE/RAGE Interaction in Patients with Pressure Overload-Induced Heart Failure

压力过载诱发心力衰竭患者中 AGE/RAGE 的相互作用

• 批准号: 8392975
• 负责人: Michael R Zile
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392975
• 关键词: Advanced Glycosylation End Products; Aftercare; Animal Model; Aortic Valve Stenosis; Binding; Biopsy; Chloride Ion; Chlorides; Chronic; Clinical; Clinical Research; Collagen; Collagen Receptors; Complementary DNA; Coronary Artery Bypass; Development; Diastolic heart failure; EFRAC; Fibroblasts; Goals; Grant Review; Healthcare; Heart failure; Hypertension; Infection; Left; Left Ventricular Hypertrophy; Ligand Binding; Ligands; Measures; MicroRNAs; Molecular; Morbidity - disease rate; Myocardial; Myocardial tissue; Myocardium; Pathway interactions; Patients; Performance; Phenotype; Play; Population; Program Reviews; Property; Proteins; Regulation; Risk Factors; Role; Signal Transduction; Signs and Symptoms; Structure; Testing; Tissues; Translations; Ventricular; Veterans; Viral; base; care burden; crosslink; disability; effective therapy; evidence based guidelines; gain of function; loss of function; mRNA Transcript Degradation; mortality; novel; pressure; prevent; public health relevance; receptor; receptor for advanced glycation endproducts; research study; response

DESCRIPTION (provided by applicant): In response to the chronic pressure-overload caused by arterial hypertension or aortic valve stenosis, the myocardium undergoes hypertrophic remodeling that results in the development of left ventricular hypertrophy (LVH). These structural changes are associated with mild - moderate alterations in diastolic performance and increased left ventricular diastolic chamber stiffness. However, these initial compensatory changes in structure and function do not result in the development of clinical heart failure; these patients have compensatory LVH. Eventually, some patients decompensate and develop clinical heart failure. In these patients, hypertrophic remodeling is associated with severe alterations in diastolic performance and severely increased myocardial stiffness; these patients have diastolic heart failure (DHF). The mechanisms that contribute to the transition from compensated LVH to decompensated DHF in patients with chronic pressure-overload are not clearly defined. DHF is a major cause of morbidity and mortality in the Veteran population. Despite this health care burden, there are no evidence based recommendations for treatment that will reduce the mortality, morbidity or disability suffered by Veterans with DHF. In large part, these deficiencies may result from the lack of clear understanding of what basic, fundamental, underlying cellular and molecular mechanisms cause DHF. The fundamental goal of my VA Merit Review program is to identify the mechanisms that cause diastolic heart failure. Based on the preliminary clinical studies in patients with aortic valve stenosis (AS) presented in this application and studies in animal models of pressure-overload performed during my previous Merit Review grants, we hypothesized that the formation of advanced glycation end products (AGEs) and their interaction with the receptor for AGEs (RAGE) are a primary determinants of myocardial stiffness, collagen structure and fibroblast phenotype. Furthermore, we hypothesized that three AGE-dependent mechanisms contribute to the transition from compensated LVH to decompensated diastolic heart failure in patients with AS. First, chronic PO causes the formation of AGEs that increase AGE-induced collagen cross-links, modify the material properties of collagen and increase myocardial stiffness. Second, chronic AGE-ligand stimulation of the RAGE receptor results in a change in fibroblast phenotype characterized by increased RAGE and collagen synthesis. Third, the change in fibroblast phenotype is dependent upon regulation of microRNAs (miRs) that effect mRNA degradation or protein translation, specifically miRs that target AGE/RAGE dependent pathways and effect RAGE and collagen synthesis. We will test these hypotheses using three Specific Aims. Specific Aim 1: Demonstrate that increased AGE- induced collagen cross-links contribute to increases in stiffness in AS patients with compensated LVH and a change in fibroblast phenotype contributes to the transition in AS patients to decompensated DHF. Specific Aim 2: Demonstrate that an increase in AGE/RAGE interaction contributes to a change fibroblast phenotype characterized by an increase in RAGE and collagen synthesis. Specific Aim 3: Demonstrate that specific endogenous microRNAs that target RAGE prevent or enhance a change in fibroblast phenotype. This completely revised proposal will more directly examine three specific AGE-dependent mechanisms that contribute to the development of compensated left ventricular hypertrophy and the transition to diastolic heart failure.

描述（由申请人提供）： 由于动脉高压或主动脉瓣狭窄引起的慢性压力超负荷，心肌发生肥厚性重构，导致左心室肥厚（LVH）的发展。这些结构变化与舒张功能的轻度-中度改变和左心室舒张室僵硬度增加有关。然而，这些结构和功能的初始代偿性变化不会导致临床心力衰竭的发展;这些患者具有代偿性LVH。最终，一些患者失代偿并发展为临床心力衰竭。在这些患者中，肥厚性重构与舒张功能的严重改变和严重增加的心肌硬度相关;这些患者患有舒张性心力衰竭（DHF）。导致慢性压力超负荷患者从代偿性LVH向失代偿性DHF转变的机制尚不清楚。登革出血热是退伍军人发病率和死亡率的主要原因。尽管有这种医疗保健负担，但没有证据表明治疗建议可以降低DHF退伍军人的死亡率，发病率或残疾。在很大程度上，这些缺陷可能是由于缺乏对导致DHF的基本，根本，潜在细胞和分子机制的清晰理解。我的VA Merit Review计划的基本目标是确定导致舒张性心力衰竭的机制。 基于本申请中提出的主动脉瓣狭窄（AS）患者的初步临床研究以及我之前的Merit Review赠款期间在压力超负荷动物模型中进行的研究，我们假设晚期糖基化终产物（AGEs）的形成及其与AGEs受体（AGEs）的相互作用是心肌硬度、胶原结构和成纤维细胞表型的主要决定因素。此外，我们假设三种AGE依赖性机制有助于AS患者从代偿性LVH向失代偿性舒张性心力衰竭的转变。首先，慢性PO导致AGEs的形成，其增加AGE诱导的胶原交联，改变胶原的材料性质并增加心肌硬度。第二，慢性AGE-配体刺激β受体导致成纤维细胞表型的变化，其特征在于β受体和胶原合成增加。第三，成纤维细胞表型的变化依赖于影响mRNA降解或蛋白质翻译的微小RNA（miR）的调节，特别是靶向AGE/AGE依赖性途径并影响AGE和胶原合成的miR。我们将用三个具体目标来检验这些假设。具体目标1：证明AGE诱导的胶原交联增加有助于伴有代偿性LVH的AS患者的硬度增加，成纤维细胞表型的变化有助于AS患者向失代偿性DHF的转变。具体目标二：证明AGE/TGF β相互作用的增加有助于改变成纤维细胞表型，其特征在于TGF β和胶原合成的增加。具体目标3：证明靶向成纤维细胞的特异性内源性microRNA预防或增强成纤维细胞表型的变化。这一完全修订的提案将更直接地研究有助于代偿性左心室肥大发展和向舒张性心力衰竭转变的三种特定的AGE依赖性机制。