Impact of AMP-activated kinase on sex differences in hypertrophic cardiomyopathy

AMP 激活激酶对肥厚型心肌病性别差异的影响

基本信息

批准号：
8011377
负责人：
JOHN P KONHILAS
金额：
$ 37.58万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011377
关键词：
5&apos -AMP-activated protein kinase ATP phosphohydrolase Accounting Address Adenosine Monophosphate Cardiac Cardiovascular Diseases Contractile Proteins Data Deterioration Disease Disease Progression Etiology Female Foundations Functional disorder Heart Heart Diseases Human Hypertension Hypertrophic Cardiomyopathy Hypertrophy Kinetics Left Link Measures Mechanics Mediator of activation protein Metabolic Microfilaments Motor Mus Muscle Mutation Myocardial Infarction Myocardium Myosin Heavy Chains Pathology Pathway interactions Phosphorylation Phosphotransferases Population Post-Translational Protein Processing Preparation Property Protein Isoforms Proteins Role Sex Characteristics Signal Transduction Site Testing Time Troponin I Ventricular Wild Type Mouse Woman Work clinically significant cost design indexing inhibitor/antagonist male men pressure public health relevance response sex sexual dimorphism

项目摘要

DESCRIPTION (provided by applicant): Sex/gender differences exist in human cardiac disease resulting from many disease etoilogies including hypertension, myocardial infarction, and hypertrophic cardiomyopathy (HCM). The hearts of women with these disorders maintain, at least, adequate cardiac function whereas men typically demonstrate increased chamber dilation and wall thinning, all signs of progressively deteriorating cardiac disease. Humans with HCM caused by an autosomal dominant mutation (R403Q) in the predominant motor protein in the heart (1-myosin heavy chain) show a similar sex difference in cardiac disease progression. Like their human counterparts, male mice expressing the R403Q mutation in the heart develop HCM characterized by progressive left-ventricular dilation and cardiac dysfunction whereas females show hypertrophy without dilation or dysfunction. However, the mechanisms that underlie these differences remain unknown. Because the R403Q mutation resides in the motor protein of the cellular contractile apparatus, hearts expressing the R403Q mutation are energy deprived and that this may be due to the increased energetic cost of contraction when expressing the R403Q mutation. Therefore, the prediction is that the observed sex difference may result from the inability of male hearts to match this increased energetic demand compared to females. In support of this idea, male R403Q hearts show metabolic abnormalities consistent with an energy-deprived state. Adenosine monophosphate-activated kinase (AMPK) may be a central regulator of this sex difference because of its established role in (1) sensing changes in cellular energy state, (2) regulating mediators of energy producing pathways, and, (3) directly modifying contractile proteins by phosphorylation. Yet, no studies have systematically addressed AMPK sex dimorphisms in mice with the R403Q mutation. Therefore, the outlined experimental plan is designed to concisely test the hypothesis that male hearts do not adapt appropriately to the increase in energetic demand caused by the R403Q HCM mutation, which leads to progressively worsening cardiac dysfunction. The hypothesis to be tested is that the key mechanism that underlies this sexual dimorphism is an altered AMPK signaling axis in males compared to females. Moreover, these studies will provide a critical foundation upon which to guide future research into defining fundamental differences in metabolic and oxidative capacities of male and female hearts in order to more completely elucidate sex differences in cardiovascular disease etiology and treatment in the human population. PUBLIC HEALTH RELEVANCE: Males and females respond differently to cardiac disease such that males typically show signs of worsening cardiac function and females do not. The way males and females uniquely handle the energetic deficiencies associated with cardiac disease underlies these differences. Therefore, it is of major clinical significance that the mechanistic link be determined between cardiac disease, sex/gender differences and energetic regulators in the heart. )

描述（由申请人提供）：许多疾病疾病引起的人性心脏病中存在性别差异，包括高血压，心肌梗塞和肥大性心肌病（HCM）。这些疾病的女性的心脏至少保持了足够的心脏功能，而男性通常表现出增加的腔室扩张和壁稀疏，这均表现出逐渐恶化的心脏病。由心脏中主要运动蛋白（1-肌球蛋白重链）中的常染色体显性突变（R403Q）引起的HCM的人在心脏病进展中显示出类似的性别差异。像他们的人类对应物一样，表达心脏R403Q突变的雄性小鼠发展为HCM，其特征是进行性左心室扩张和心脏功能障碍，而女性则在没有扩张或功能障碍的情况下表现出肥大。但是，这些差异基础的机制仍然未知。由于R403Q突变位于细胞收缩设备的运动蛋白中，因此表达R403Q突变的心脏被剥夺了能量，这可能是由于表达R403Q突变时的收缩成本增加所致。因此，预测是，与女性相比，观察到的性别差异可能是由于男性心脏无法符合这种能量需求增加的能力而导致的。为了支持这一想法，男性R403Q心脏显示出与能量剥夺状态一致的代谢异常。腺苷单磷酸激活的激酶（AMPK）可能是这种性别差异的中心调节剂，因为它在（1）感应细胞能状态的感觉变化中，（2）调节能量产生途径的介体，以及（3）通过磷酸化直接修饰收缩蛋白。然而，没有研究在具有R403Q突变的小鼠中系统地解决了AMPK性二态性。因此，概述的实验计划旨在简洁地检验以下假设：雄性心脏不能适当适应由R403Q HCM突变引起的能量需求的增加，从而导致心脏功能障碍逐渐恶化。要检验的假设是，与女性相比，这种性二态性基础的关键机制是男性的AMPK信号轴改变。此外，这些研究将为未来的研究提供一个关键的基础，以定义男性和女性心脏代谢和氧化能力的基本差异，以便更彻底地阐明人口中心血管疾病病因和治疗的性别差异。公共卫生相关性：男性和女性对心脏疾病的反应不同，因此雄性通常显示出恶化的心脏功能，而女性则没有。雄性和女性独特地处理与心脏病相关的能量缺陷的方式是这些差异。因此，确定心脏疾病，性别差异和心脏能量调节剂之间的机械联系是至关重要的临床意义。）