AGE/RAGE Interaction in Patients with Pressure Overload-Induced 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)。这些结构变化与舒张期表现的轻-中度改变和左心室舒张室僵硬增加有关。然而，这些最初的结构和功能的代偿性改变并不会导致临床心力衰竭的发展；这些患者有代偿性左室肥厚。最终，一些患者会失代偿并发展为临床心力衰竭。在这些患者中，肥厚重构与舒张期性能的严重改变和心肌僵硬的严重增加有关；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向失代偿性DHF转变的机制尚不清楚。DHF是退伍军人中发病率和死亡率的主要原因。尽管有这种医疗负担，但没有基于证据的治疗建议来降低患有DHF的退伍军人的死亡率、发病率或残疾。在很大程度上，这些缺陷可能是由于缺乏对引起DHF的基本、基本、潜在的细胞和分子机制的清楚了解。我的VA功绩评估计划的基本目标是确定导致舒张性心力衰竭的机制。根据本申请中介绍的对主动脉瓣狭窄(AS)患者的初步临床研究，以及在我之前的功绩评估资助期间进行的压力超负荷动物模型研究，我们假设晚期糖基化终产物(AGEs)的形成及其与AGEs受体(RAGE)的相互作用是心肌僵硬、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AS患者从代偿性LVH到失代偿性舒张性心力衰竭的转变有三种年龄依赖性机制。首先，慢性PO导致AGEs的形成，增加了AGE诱导的胶原交联度，改变了胶原的材料性质，增加了心肌硬度。其次，RAGE受体的慢性AGE配体刺激导致以RAGE和胶原合成增加为特征的成纤维细胞表型的改变。第三，成纤维细胞表型的改变依赖于影响mRNA降解或蛋白质翻译的microRNAs(MiRs)的调节，特别是针对AGE/RAGE依赖的途径并影响RAGE和胶原合成的miRs。我们将使用三个具体目标来检验这些假设。具体目标1：证明增龄诱导的胶原交联物增加有助于代偿性左心室肥厚的AS患者僵硬程度的增加，成纤维细胞表型的改变有助于AS患者向失代偿性DHF的转变。具体目标2：证明AGE/RAGE相互作用的增加有助于以RAGE和胶原合成增加为特征的成纤维细胞表型的改变。具体目标3：证明靶向RAGE的特定内源性microRNAs阻止或促进成纤维细胞表型的改变。这一完全修订的建议将更直接地研究三种特定的年龄相关机制，这些机制有助于代偿性左心室肥厚的发展和向舒张性心力衰竭的过渡。

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.