The Role of Histone Deacytelases in Right Ventricular Adaptation in Hypoplastic L

组蛋白脱乙酰酶在发育不全 L 细胞右心室适应中的作用

• 批准号: 8445748
• 负责人: CARLIN S LONG
• 金额: $ 24.46万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445748
• 关键词: ATP phosphohydrolase; Adult; Animal Model; Atrial Natriuretic Factor; Blood Circulation; Calcium; Calmodulin; Cardiac; Cardiovascular system; Cause of Death; Cessation of life; Child; Childhood; Chronic; Clinical; Clinical Trials; Common Ventricle; Complex; Congenital Abnormality; Congenital Heart Defects; Consensus; Data; Defect; Diagnosis; Distal; Down-Regulation; Enalapril; Enrollment; Enzymes; Epigenetic Process; Failure; Fibrosis; Functional disorder; Gene Expression Profile; Growth; Guidelines; Heart; Heart Transplantation; Heart failure; Histones; Human; Hypertrophy; Hypoplastic Left Heart Syndrome; Hypoxia; Infant; Intervention; Lead; Left; Left ventricular structure; Lesion; Link; Lysine; Mediating; Medical; Modeling; Morphology; Myocardial; Myocardium; Myosin Heavy Chains; Neonatal; Outcome; Pathologic; Pathway interactions; Phosphorylation; Phosphotransferases; Physiology; Placebos; Play; Population; Process; Protein Isoforms; Proteins; Pulmonary Circulation; Pump; Randomized Controlled Trials; Rattus; Recommendation; Regulation; Right Ventricular Function; Right ventricular structure; Role; Sarcoplasmic Reticulum; Side; Signal Pathway; Site; Stimulus; Stress; Structure; Survival Rate; Therapeutic; Tissue Banking; Tissue Banks; Up-Regulation; Ventricular; Vulnerable Populations; base; carvedilol; congenital heart disorder; experience; improved; infancy; inhibitor/antagonist; mRNA Expression; new therapeutic target; pressure; public health relevance; randomized trial; receptor; response; trend

DESCRIPTION (provided by applicant): Hypoplastic Left Heart Syndrome (HLHS) is the most common form of severe congenital heart disease and is the leading cause of cardiovascular death in infancy. HLHS comprises a spectrum of congenital malformations characterized by severe underdevelopment of all left-sided heart structures including a diminutive left ventricle (LV). This results in a univentricular circulation with the morphologic right ventricle (RV) servin as the pump to both the systemic and pulmonary circulations. This defect is universally fatal without intervention and although outcomes are improving, HLHS remains a devastating diagnosis with one-year survival rates of only 40-60%. Not surprisingly, failure of the single RV is both a common cause of death and indication for a heart transplant in infants and children with HLHS. Historically, pharmacologic treatment of heart failure in the pediatric population has largely been extrapolated from the adult heart failure experience and treatment guidelines are based primarily on expert consensus. Importantly two recent clinical trials have demonstrated that children with a systemic right ventricle (ie HLHS) do not receive any clinical benefit from either enalapril or carvedilol therapy over placebo. This evidence suggests that: [1] continued extrapolation of adult data as the basis for treatment of heart failure in children is not appropriate, [2] ventricular morphology and complex congenital heart disease are important considerations in heart failure treatment and [3] identification of novel therapeutic targets are necessary to improve outcomes in this vulnerable population. Histone deacytelases (HDACs) are enzymes that deacetylate lysine on histone and non-histone proteins and have been linked to many different processes in the failing heart. The importance of epigenetic regulation of cardiac adaptation is evident in some animal models of heart failure, where HDAC inhibitors block pathologic hypertrophy and fibrosis while improving cardiac function. The role of HDACs in human heart failure is incompletely understood, and has never been investigated in pediatric heart failure or in congenital heart disease. The central hypothesis of this proposal is that HDACs play a role in mediating pathologic adaptation of a right ventricle exposed to chronic hypoxia and pressure overload. Therefore the purpose of the current proposal is to use our existing pediatric heart tissue bank to determine the expression and catalytic activity of specific HDAC isoforms in the right ventricular myocardium of children with HLHS. In addition, we aim to characterize the role of specific HDAC isoforms and HDAC-inhibitor treatment on pathologic remodeling of the right ventricle in hypoxic neonatal rats (as a model of HLHS). Modulation of HDAC activity, given the distal site of action in the signaling pathway, could have unique therapeutic potential in RV failure in HLHS.

描述（由申请人提供）：左心发育不良综合征（HLHS）是最常见的严重先天性心脏病，也是婴儿期心血管死亡的主要原因。 HLHS 包括一系列先天性畸形，其特征是所有左侧心脏结构严重发育不良，包括小型左心室 (LV)。这导致单心室循环，形态学右心室（RV）作为体循环和肺循环的泵。如果不进行干预，这种缺陷通常是致命的，尽管结果正在改善，但 HLHS 仍然是一个毁灭性的诊断，一年生存率仅为 40-60%。毫不奇怪，单个 RV 衰竭既是 HLHS 婴儿和儿童死亡的常见原因，也是进行心脏移植的指征。从历史上看，儿童心力衰竭的药物治疗很大程度上是根据成人心力衰竭的经验推断的，治疗指南主要基于专家共识。重要的是，最近的两项临床试验表明，与安慰剂相比，患有全身性右心室（即 HLHS）的儿童不会从依那普利或卡维地洛治疗中获得任何临床益处。该证据表明：[1]继续外推成人数据作为儿童心力衰竭治疗的基础是不合适的，[2]心室形态和复杂的先天性心脏病是心力衰竭治疗的重要考虑因素，[3]识别为了改善这一弱势群体的治疗结果，需要新的治疗目标。组蛋白脱乙酰酶 (HDAC) 是一种使组蛋白和非组蛋白上的赖氨酸脱乙酰的酶，与衰竭心脏中的许多不同过程有关。心脏适应的表观遗传调控的重要性在一些心力衰竭动物模型中显而易见，其中 HDAC 抑制剂可阻止病理性肥大和纤维化，同时改善心脏功能。 HDAC 在人类心力衰竭中的作用尚不完全清楚，并且从未在儿科心力衰竭或先天性心脏病中进行过研究。该提议的中心假设是 HDAC 在介导右心室慢性缺氧和压力超负荷的病理适应中发挥作用。因此，当前提案的目的是利用我们现有的儿科心脏组织库来确定特定的表达和催化活性。 HLHS 儿童右心室心肌中的 HDAC 亚型。此外，我们的目的是表征特定 HDAC 亚型和 HDAC 抑制剂治疗对缺氧新生大鼠（作为 HLHS 模型）右心室病理重塑的作用。考虑到信号通路中的远端作用位点，调节 HDAC 活性可能对 HLHS 右心室衰竭具有独特的治疗潜力。