CYTOSKELETON AND CONTRACTILE DYSFUNCTION IN HYPERTROPHY

这个项目的最初目标是确定细胞骨架是否 这些改变在肥厚性心肌的收缩功能障碍中起作用， 如果是这样的话，他们的性格，他们的位置，他们的原因是什么。 重要的成就是1）微管的展示- 心肌肥厚和 RV和LV衰竭，2）这些发现扩展到孤立组织， 完整心脏，3）病因学的生物物理学特征 基于微管的收缩功能障碍，4）这一发现， 病理生理机制严格限于压力超负荷- 诱导肥大，其中壁应力增加，5） 证明微管是唯一的主要肌丝外 细胞骨架蛋白受到影响，6）发现这种现象是 基于微管蛋白和微管的增加， 稳定性的微管一旦形成，7）发现，主要的 心肌微管稳定蛋白在心肌细胞中显著上调， 压力超负荷心脏肥大，8）发现，转录， 在肥大过程中两种次要的β-微管蛋白亚型的上调， 我们发现模仿这些基因的发育调节， 增加β-微管蛋白，和9）证明，其中一个 这些异构体可以与MAP 4协同作用， 压力超负荷心肌肥大中的微管。的第一个目标 提出的工作是减少之间的相关关系 微管网络致密化和心脏收缩功能障碍， 通过直接的基因操作， 微管的稳定性，并通过探索的作用，改变 编码微管和微管相关蛋白的基因的表达 蛋白质发现至今第二个目标是扩大调查范围 从微管对心肌细胞组成特性的影响， 考虑对心肌细胞更特异的微管依赖性作用 本构性质的考虑更具体的微管- 对肥大细胞的依赖性影响，明确地说， 考虑心肌细胞密度增加的任何作用 β-肾上腺素能受体脱敏中的微管网络 心脏肥大的特征。

The initial goals of this project were to determine whether cytoskeletal alterations have a role in the contractile dysfunction of hypertrophied myocardium, and if so, what is their nature, their locus, and their cause. Important accomplishments have been 1) the demonstration of microtubule- based contractile dysfunction in cardiocytes from the hypertrophied and failing RV and LV, 2) extension of these findings to isolated tissue and to the intact heart, 3) biophysical characterization of the etiology of the microtubule-based contractile dysfunction, 4) the finding that this pathophysiological mechanism is tightly restricted to pressure overload- induced hypertrophy in which wall stress is increased, 5) the demonstration that microtubules are the only major extra-myofilament cytoskeletal protein so affected, 6) the finding that this phenomenon is based both on increased tubulin, and thus microtubules, and on increased stability of the microtubules once formed, 7) the finding that the major cardiac microtubule-stabilizing protein is markedly up-regulated in pressure overload cardiac hypertrophy, 8) the finding that transcriptional upregulation of two minor beta-tubulin isoforms during hypertrophy, which we found to mimic the developmental regulation of these genes, accounts for the increase in beta-tubulin, and 9) the demonstration that one of these isoforms may act synergistically with MAP 4 to stabilize microtubules in pressure overload cardiac hypertrophy. The first goal of the work proposed is to reduce the correlative relationship between microtubule network densification and cardiac contractile dysfunction to a cause-and-effect relationship via direct genetic manipulation of microtubule stability and via an exploration of the role of altered expression of genes encoding microtubule and microtubule-associated proteins found to date. The second goal is to extend this investigation from microtubule effects on cardiocyte constitutive properties to a consideration of more specific microtubule-dependent effects on cardiocyte constitutive properties to a consideration of more specific microtubule- dependent effects on the hypertrophied cell, and explicitly, a consideration of any role of increased density of the cardiocyte microtubule network in the beta-adrenergic receptor desensitization characteristic of cardiac hypertrophy.