ALTERATIONS IN DYNAMIC MYOFIBRILLAR FUNCTION

动态肌原纤维功能的改变

• 批准号: 2735330
• 负责人: MATTHEW R WOLFF
• 金额: $ 19.7万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2735330
• 关键词: beta adrenergic receptor; beta antiadrenergic agent; calcium flux; disease /disorder model; dogs; flash photolysis; heart cell; heart failure; heart function; human tissue; laser spectrometry; molecular pathology; muscle relaxation; muscle tension; myocardium; myocardium disorder; myofibrils; nonhuman therapy evaluation; phosphorylation; sarcomeres

DESCRIPTION (adapted from the applicant's abstract): The overall goal of the principal investigator is to relate the depression of ventricular function in human and experimental canine dilated cardiomyopathy to alterations in the mechanical behavior of the cardiac myofibril. Previous experiments by the applicant have demonstrated that the calcium sensitivity of isometric tension is increased in both forms of heart failure, and suggested that this increase is due to reductions in b- adrenergically mediated (protein kinase A-dependent) phosphorylation of myofibrillar proteins. Prior studies in normal myocardium suggest that protein kinase A-mediated phosphorylation of myofilament proteins results in important alterations in dynamic as well as isometric myofibrillar mechanical function, increasing unloaded or maximal velocity of shortening and accelerating the rates of tension development and myofibrillar relaxation. The central hypothesis of this proposal, therefore, is that reductions in the basal level of b-adrenergically mediated phosphorylation of myofilament proteins results in significant alterations in dynamic myofibrillar function, including reduced shortening velocities under physiologic loads, reduced maximal myofibrillar power output, and decreased rates of isometric tension development and myofibrillar relaxation. These hypotheses will be tested in myocyte-sized myofibrillar preparations from failing and non-failing human and canine myocardium, using techniques such as laser diffraction methods to monitor and control sarcomere lengths, and UV flash photolysis to rapidly change activator calcium concentrations. In the canine model of chronic rapid pacing-induced heart failure, changes in dynamic myofibrillar function will be directly related to alterations in myofibrillar protein phosphorylation, and to depression of left ventricular systolic and diastolic function. A second hypothesis is that chronic oral b-adrenergic blockade in dilated cardiomyopathy will limit the severity of contractile failure, increase basal phosphorylation of myofilament proteins, and normalize maximal myofibrillar power output and other indices of myofibrillar mechanical function in this model. This hypothesis will be tested in the canine chronic rapid pacing model using similar techniques.

描述(改编自申请者的摘要)：总体目标 主要研究者的观点是与脑室压低有关 在人和实验性犬扩张型心肌病中的作用 心肌原纤维力学行为的改变。 申请人之前的实验已经证明，钙 在这两种类型的心脏中，等长张力的敏感性都增加了 失败，并认为这一增长是由于b- 肾上腺素介导的(蛋白激酶A依赖的)磷酸化 肌原纤维蛋白。先前对正常心肌的研究表明， 蛋白激酶A介导的肌丝蛋白磷酸化 导致动态和等轴测的重要变化 肌原纤维机械功能增加，无负荷或最大 缩短和加快张力发展的速度 和肌原纤维松弛。这一提议的核心假设是， 因此，b-肾上腺素基础水平的降低 介导的肌丝蛋白的磷酸化导致显著 动态肌原纤维功能的改变，包括降低 生理负荷下收缩速度最大减速 肌原纤维的功率输出和等长张力降低 发育和肌原纤维松弛。这些假说将得到检验。 在肌细胞大小的肌原纤维制剂中 人和狗的心肌，使用激光衍射等技术 监测和控制肌节长度和紫外线闪光的方法 光解作用能迅速改变激活剂的钙浓度。在 犬慢性快速起搏所致心力衰竭模型的变化 动态肌原纤维功能将与改变直接相关 在肌原纤维蛋白的磷酸化，并对左 心脏收缩和舒张期功能。第二个假设是 慢性口服β-肾上腺素能阻断治疗扩张型心肌病将 限制收缩衰竭的严重程度，增加基础 肌丝蛋白的磷酸化，最大正常化 肌原纤维功率输出等肌原纤维力学指标 在此模型中的功能。这一假说将在犬类身上进行验证。 使用类似技术的慢性快速起搏模型。