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）：我们对病理和生理肥厚性心脏对血液动力学挑战的负荷特异性的研究导致了发现[Science，260：682-687，1993]在致病性的，高心脏壁压力过量的严重造成的造成严重的压力范围内，造成了严重的心脏细胞微管网络，导致了严重的造成促进的造成促进的促进，并促进造成促进的促进效果。在这种情况下发生。为了确定这种细胞骨架异常的原因，我们从未见过微管网络随着同等补偿的生理肥大的等效程度和持续时间的变化而提供了一个关键的提示，其中室中心壁应力保持正常。这个提示，再加上以下三个考虑因素，导致了本申请中提出的研究。首先，致病性心脏肥大的标志是循环和神经儿茶酚胺的持续升高，因此人们期望这在病理肥大中存在，但没有补偿的生理肥大。其次，最近的数据在增加p21激活激酶或PAK1的活性中建立了B-肾上腺素能力输入的关键作用，而P21激活激酶或PAK1的活性又引发了磷酸酶激活的级联激活，特别是PP2A，然后是PP1。第三，我们自己的数据表明，在病理心脏肥大中看到的异常微管网络是由与MAP4（主要心脏微管相关结构蛋白）结合的驱动的，而这反过来又由磷酸酶依赖性磷酸酶特异性位点特异性MAP4去磷酸化。我们建议以两个具体目的在这里使用此信息。在特定的目标＃1中，我们将尝试通过比较我们猫科学生理体积超负荷肥大的良好表征模型与我们具有慢性bl-byadrenrenergric blognect型的病理压力超载肥大模型，从而确定B-肾上腺素能力输入在引起肥大相关的心脏微管表型中的病因作用。如果正确的话，我们的假设将预测异常的微管网络将存在于没有B-肾上腺素能阻断的情况下压力过多的肥大中，但在该模型中都没有B-肾上腺素能阻断和没有药物治疗的生理体积量超载模型。在特定的目标＃2中，如果我们能够通过使用慢性B-肾上腺素能阻断在其特征的严重压力超载模型中使用慢性B-肾上腺素能阻断来防止形成密集的MAP4装饰的微管网络，我们将确定这是否还可以防止相关的功能异常和基于微管的运输。公共卫生相关性：充血性心力衰竭是65岁或更高的美国人入院和入院的主要原因。表征收缩性心力衰竭的收缩功能障碍和心脏生长异常是对几种病理挑战的不良适应性心肌反应，包括持续的心压超负荷。这项研究将确定失败心脏功能障碍的重要原因的基本机制：心脏肌肉细胞细胞骨架的微管网络的改变。