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: 8257862
• 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/8257862
• 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. PUBLIC HEALTH RELEVANCE: The most common cause of CV morbidity and mortality in the Veteran population is chronic heart failure (HF). LV pressure-overload (hypertension and aortic valve stenosis) is the largest risk factor for the development of HF. Over 50% of HF patients develop symptoms and signs of clinical HF despite a normal (or preserved) ejection fraction. These patients are said to have diastolic heart failure (DHF). Patients with DHF have an enormous increase in mortality, morbidity, and disability. Despite this unmet health care burden, there is no effective treatment for these Veterans with DHF. This lack of effective treatment is caused by the fact that we do not have a clear understanding of what basic, fundamental, underlying cellular and molecular mechanisms cause DHF. My goal is to identify the mechanisms that cause pressure-overload induced DHF and then to use these mechanisms as a target to develop novel, effective treatment for VA patients with heart failure.

描述（由申请人提供）： 为了应对动脉高血压或主动脉瓣狭窄引起的慢性压力超负荷，心肌会发生肥厚重塑，导致左心室肥厚 (LVH)。这些结构变化与舒张功能的轻度至中度改变和左心室舒张室硬度增加相关。然而，这些最初的结构和功能代偿性变化不会导致临床心力衰竭的发展；这些患者有代偿性 LVH。最终，一些患者失代偿并出现临床心力衰竭。在这些患者中，肥厚性重塑与舒张功能的严重改变和心肌僵硬度的严重增加有关。这些患者患有舒张性心力衰竭（DHF）。慢性压力超负荷患者从代偿性 LVH 转变为失代偿性 DHF 的机制尚不清楚。 DHF 是退伍军人发病和死亡的主要原因。尽管存在医疗保健负担，但没有基于证据的治疗建议可以降低患有 DHF 的退伍军人所遭受的死亡率、发病率或残疾。在很大程度上，这些缺陷可能是由于对导致 DHF 的基本、根本、潜在的细胞和分子机制缺乏清晰的了解所致。我的退伍军人管理局绩效审查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优异评审资助期间进行的压力超载动物模型研究，我们假设晚期糖基化终末产物 (AGE) 的形成和它们与 AGE 受体 (RAGE) 的相互作用是心肌僵硬度、胶原蛋白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 会导致 AGE 的形成，从而增加 AGE 诱导的胶原蛋白交联，改变胶原蛋白的材料特性并增加心肌僵硬度。其次，RAGE 受体的慢性 AGE 配体刺激会导致成纤维细胞表型发生变化，其特征是 RAGE 和胶原蛋白合成增加。第三，成纤维细胞表型的变化取决于影响 mRNA 降解或蛋白质翻译的 microRNA (miR) 的调节，特别是靶向 AGE/RAGE 依赖性途径并影响 RAGE 和胶原蛋白合成的 miR。我们将使用三个具体目标来测试这些假设。具体目标 1：证明 AGE 诱导的胶原交联增加导致代偿性 LVH 的 AS 患者硬度增加，而成纤维细胞表型的变化导致 AS 患者向失代偿性 DHF 转变。具体目标 2：证明 AGE/RAGE 相互作用的增加有助于改变以 RAGE 和胶原合成增加为特征的成纤维细胞表型。具体目标 3：证明针对 RAGE 的特定内源性 microRNA 可预防或增强成纤维细胞表型的变化。这项经过彻底修改的提案将更直接地检查三种特定的 AGE 依赖性机制，这些机制有助于代偿性左心室肥大的发展和向舒张性心力衰竭的转变。 公共卫生相关性： 退伍军人群体中心血管发病和死亡的最常见原因是慢性心力衰竭（HF）。左心室压力超负荷（高血压和主动脉瓣狭窄）是发生心力衰竭的最大危险因素。尽管射血分数正常（或保留），但超过 50% 的心力衰竭患者会出现临床心力衰竭的症状和体征。据说这些患者患有舒张性心力衰竭（DHF）。 DHF 患者的死亡率、发病率和残疾率大幅增加。尽管医疗保健负担未得到满足，但这些患有 DHF 的退伍军人仍没有有效的治疗方法。缺乏有效的治疗是因为我们对导致 DHF 的基本、根本、潜在的细胞和分子机制没有清楚的了解。我的目标是确定导致压力超负荷诱发 DHF 的机制，然后以这些机制为目标，为患有心力衰竭的 VA 患者开发新颖、有效的治疗方法。