Beta-Adrenergic Control of the Pathological Cardiac Microtubule Network

病理性心脏微管网络的β-肾上腺素能控制

基本信息

批准号：
7952783
负责人：
GEORGE COOPER
金额：
$ 22.13万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2010-07-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7952783
关键词：
Adenosine Admission activity Adrenergic Agents Adrenergic Antagonists Affect Aftercare Age American Attenuated Binding Biopsy Canis familiaris Cardiac Cardiac Myocytes Catecholamines Cell Nucleolus Cell Nucleus Cells Characteristics Chronic Clinical Treatment Colchicine Congestive Heart Failure Control Animal Coupled Cytoskeleton Data Dependence Depressed mood Development Electrons Employee Strikes Etiology Failure Family Felidae Felis catus Functional disorder Genetic Transcription Genetic screening method Growth Heart Heart Diseases Heart Hypertrophy Heart failure Hospitals Human Hypertrophy Institutes Intracellular Transport Kinesin Knowledge Left Left Ventricular Mass Left ventricular structure MAP4 Measures Mechanics Mediating Microfilaments Microtubule Depolymerization Microtubules Modeling Motor Myocardial Myocardium Myofibrils Normal Cell Outcome Patients Pharmaceutical Preparations Phase Phenotype Phosphoric Monoester Hydrolases Physiological Prevention Protein Biosynthesis Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Publishing Research Ribosomes Right ventricular structure Right-On Role Sarcomeres Science Series Site Specificity Staining method Stains Stress Structural Protein System Systolic heart failure Time Transport Process Tubulin Ventricular Work adrenergic aged base density early onset editorial experience hemodynamics interest messenger ribonucleoprotein p21 activated kinase p21-activated kinase 1 pressure prevent public health relevance relating to nervous system response

项目摘要

DESCRIPTION (provided by applicant): Our studies of the load-specificity of pathological versus physiological hypertrophic cardiac responses to hemodynamic challenges led to the discovery [Science, 260: 682-687, 1993] of a dense cardiocyte microtubule network during pathological, high ventricular wall stress hypertrophy caused by severe pressure-overloading that contributes to the striking contractile and intracellular transport dysfunction that occur in this setting. In attempting to identify the cause for this cytoskeletal abnormality, a crucial hint was provided by the fact that we have never seen microtubule network changes with an equivalent degree and duration of fully compensated physiological hypertrophy wherein ventricular wall stress remains normal. This hint, coupled with the following three further considerations, led to the studies proposed in this application. First, a hallmark of decompensated pathological cardiac hypertrophy is a persistent elevation of circulating and neural catecholamines, such that one would expect this to be present in pathological hypertrophy but absent from compensated physiological hypertrophy. Second, very recent data establish a critical role of b-adrenergic input in increasing the activity of p21-activated kinase, or Pak1, which in turn initiates a cascade of phosphatase activation, specifically of PP2A and then PP1, in the heart. Third, our own data indicate that the abnormal microtubule network seen in pathological cardiac hypertrophy is driven by binding to microtubules of MAP4, the predominant cardiac microtubule-associated structural protein, and that this in turn is driven by phosphatase-dependent site-specific MAP4 dephosphorylation. We propose to use this information here in two specific aims. In Specific Aim #1, we will attempt to establish the etiological role of b-adrenergic input in causing the hypertrophy- associated cardiac microtubule phenotype by comparing our very well characterized model of feline physiological volume-overload hypertrophy to our equally well characterized model of pathological pressure-overload hypertrophy with or without chronic b-adrenergic blockade. If correct, our hypothesis would predict that the abnormal microtubule network will be present in pressure-overload hypertrophy without b-adrenergic blockade but absent both in this model with b-adrenergic blockade and in the physiological volume-overload model with no drug treatment. In Specific Aim #2, if we are able in the previous aim to prevent formation of the dense, MAP4-decorated microtubule network by using chronic b-adrenergic blockade in the severe pressure-overload model of which it is characteristic, we will determine whether this also prevents the associated functional abnormalities of contraction and microtubule-based transport. PUBLIC HEALTH RELEVANCE: Congestive heart failure is the leading cause of hospital admission and readmission in Americans aged 65 or greater. The contractile dysfunction and cardiac growth abnormalities that characterize systolic heart failure are a maladaptive myocardial response to several pathological challenges, including sustained cardiac pressure overloading. This study will identify the mechanism underlying one important cause for this dysfunction in the failing heart: alterations in the microtubule network of the cardiac muscle cell cytoskeleton.

描述（由申请人提供）：我们对病理性与生理性肥厚心脏对血流动力学挑战的反应的负荷特异性的研究导致了病理性高心室期间致密心肌细胞微管网络的发现[Science, 260: 682-687, 1993]由严重的压力过载引起的壁应力肥大导致在这种情况下发生的显着的收缩和细胞内运输功能障碍。在试图确定这种细胞骨架异常的原因时，我们从未见过微管网络发生与完全代偿的生理肥大同等程度和持续时间的变化，其中心室壁应力保持正常，这一事实提供了一个重要的提示。这一提示，加上以下三个进一步的考虑，导致了本申请中提出的研究。首先，失代偿性病理性心脏肥大的一个标志是循环和神经儿茶酚胺持续升高，因此人们预计这种情况会出现在病理性肥厚中，但在代偿性生理性肥厚中不存在。其次，最近的数据证实，β-肾上腺素能输入在增加 p21 激活激酶或 Pak1 的活性方面发挥着关键作用，Pak1 反过来又启动磷酸酶激活的级联反应，特别是心脏中的 PP2A，然后是 PP1。第三，我们自己的数据表明，病理性心脏肥大中出现的异常微管网络是通过与 MAP4（主要的心脏微管相关结构蛋白）的微管结合驱动的，而这又是由磷酸酶依赖性位点特异性 MAP4 去磷酸化驱动的。我们建议将此信息用于两个特定目标。在具体目标#1中，我们将通过将我们非常明确的猫科动物生理性体积超负荷肥大模型与我们同样明确的病理学模型进行比较，尝试确定β-肾上腺素能输入在引起肥大相关的心脏微管表型中的病因学作用。压力超负荷肥大伴或不伴慢性β-肾上腺素能阻滞。如果正确，我们的假设将预测异常微管网络将出现在没有β-肾上腺素能阻断的压力超负荷肥大中，但在有β-肾上腺素能阻断的模型和没有药物治疗的生理容量超负荷模型中都不存在。在具体目标#2中，如果我们能够在先前的目标中通过在其特征性的严重压力超负荷模型中使用慢性β-肾上腺素能阻断来防止致密的、MAP4修饰的微管网络的形成，我们将确定是否这也可以防止收缩和基于微管的运输的相关功能异常。公共卫生相关性：充血性心力衰竭是 65 岁或以上美国人入院和再入院的主要原因。以收缩性心力衰竭为特征的收缩功能障碍和心脏生长异常是心肌对多种病理挑战（包括持续心脏压力超负荷）的适应不良反应。这项研究将确定导致衰竭心脏功能障碍的一个重要原因的机制：心肌细胞细胞骨架的微管网络的改变。