Regulation of power output in cardiac myocytes

心肌细胞功率输出的调节

• 批准号: 7176875
• 负责人: Kerry S McDonald
• 金额: $ 10.13万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176875
• 关键词: Address; Adrenergic Agents; Adult; Affect; Cardiac Myocytes; Cardiac Myosins; Cardiac Output; Cardiovascular Abnormalities; Cyclic AMP-Dependent Protein Kinases; Dependence; Development; Genes; Goals; Heart; Heart failure; Human; Individual; Isometric Exercise; Laboratories; Measurement; Measures; Mechanics; Mediating; Molecular; Mus; Muscle; Muscle Cells; Myocardial; Myosin ATPase; Myosin Heavy Chains; Output; Patients; Phosphorylation; Physiological; Population; Preparation; Production; Property; Protein Analysis; Protein Isoforms; Proteins; Purpose; Range; Rate; Rattus; Reagent; Records; Regulation; Skin; Stroke Volume; Structure; Testing; Thyroid Hormones; Troponin I; Variant; Ventricular Cardiac alpha-Myosin; Work; adrenergic; beta-Myosin; blood pump; extracellular; hemodynamics; improved; insight; myosin-binding protein C; research study; response

DESCRIPTION (provided by applicant): The overall purpose of this project is to determine the cellular mechanisms that determine power output of me heart. A major focus of this proposal is determination of how variable expression of the two cardiac myosin heavy chain (MyHC) isoforms regulates contractile properties of cardiac myocytes. MyHC content will be manipulated over the entire range of 100% alpha-MyHC to 100% beta-MyHC by thyroid hormone-dependent expression of MyHC isoforms in rats. Definitive relationships between MyHC content and mechanical properties will be achieved by SDS-PAGE analysis of protein composition of individual myocytes following functional measurements. The specific aims of this study include determination of the effects of MyHC on Ca2+ sensitivity of stead:-state isometric force, loaded shortening velocity and power output. Another aim is to assess the chemomechanical steps of the myosin cross-bridge cycle that are most important in determining myocyte power output over a wide range of loads. These experiments will utilize reagents that increase the population of specific cross-bridge states, to examine how specific chemomechanical states alter power-load curves. Another aim is to determine if myocardial variations in force and power output in response to protein kinase A (PKA)-induced phosphorylation of myofibrillar proteins differ between alpha-MyHC and beta-MyHC myocytes and to determine whether phosphorylation of myosin binding protein-C is necessary for increased myofibrillar power output following beta-adrenergic stimulation. A final aim is determine the effects of PKCe-induced phosphorylation on myofibrillar power output. Overall, these experiments should provide important insights into the cellular and molecular factors that regulate power output in the heart and should improve our understanding the functional consequences of reduced expression of alpha-MyHC and altered phosphorylation states of myofibrillar proteins, which both occur during the progression of human heart failure.

描述(由申请人提供)： 这个项目的总体目的是确定决定心脏功率输出的细胞机制。这一建议的一个主要焦点是确定两个心肌肌球蛋白重链(MyHC)亚型的不同表达如何调节心肌细胞的收缩特性。通过大鼠甲状腺激素依赖的MyHC亚型的表达，MyHC的含量将在100%α-MyHC到100%β-MyHC的整个范围内被操纵。在功能测量后，通过对单个心肌细胞的蛋白质组成进行SDS-PAGE分析，将获得MyHC含量和机械性能之间的明确关系。本研究的具体目的包括测定MyHC对稳态钙敏感性的影响：-状态等长力、负荷缩短率和功率输出。另一个目的是评估肌球蛋白跨桥循环的化学机械步骤，这些步骤在决定大范围负荷下的肌细胞功率输出中是最重要的。这些实验将利用增加特定跨桥状态数量的试剂，来检查特定的化学机械状态如何改变功率-负载曲线。另一个目的是确定蛋白激酶A(PKA)诱导的肌原纤维蛋白的磷酸化在α-MyHC和β-MyHC心肌细胞中的力量和功率输出的变化是否不同，并确定肌球蛋白结合蛋白-C的磷酸化是否是在β-肾上腺素能刺激后增加肌纤维输出功率所必需的。最终目的是确定PKCE诱导的磷酸化对肌原纤维功率输出的影响。总体而言，这些实验应该为调节心脏功率输出的细胞和分子因素提供重要的见解，并应该提高我们对α-MyHC表达减少和肌原纤维蛋白磷酸化状态改变的功能后果的理解，这两种情况都发生在人类心力衰竭的进展过程中。