CARDIAC MECHANICS & ENERGETICS CORRELATED TO ISOMYOSINS

肌球蛋白是一种主要的收缩性蛋白，参与肌球蛋白的生成。 机械力和心肌纤维缩短。 多 存在心肌肌球蛋白的异构形式，每种形式都表现出特征性的 生物化学和机械性能。 异肌球蛋白组合物， 响应于许多生理和病理因素，包括 发育阶段、甲状腺激素和心室负荷。 然而，在这方面， 这种异肌球蛋白组成和内在的 完整左心室的机械和代谢特性 未知 此外，尚不清楚异肌球蛋白的变化是否 组成代表了生理适应的过程，在完整的 器官水平，以及这种适应是否变得不充分， 心脏循环状况的组合（即，舒张末期容积， 动脉负荷和心率），导致左心室功能衰竭 脑室 因此，本建议的两个主要目标是： 检查异肌球蛋白组成的变化与 左心室的固有机械和代谢特性;以及 ii）评估改变异肌球蛋白组成对总体 左心室的表现。 为了确定是否有 存在“唯一”关系（即，独立于刺激因素） 异肌球蛋白组成的变化与机械和代谢 左心室的性质，将检查几种动物模型; 甲状腺功能减退和甲状腺功能亢进（大鼠和兔）;以及压力超负荷 （兔的主动脉缩窄和大鼠的自发性高血压）。 此外，为了分析肥大单独对 那些由于异肌球蛋白组成的变化，压力超负荷， 模型将进一步研究，其中异肌球蛋白组成保持恒定， 伴随甲状腺激素状态的操纵。 机械 将评估两种特性（收缩弹性和阻力） 原位和在离体心脏制备中。 代谢特性 将在离体心脏研究中通过将心肌氧 对外部机械功和收缩压容积的消耗 区 将分析异肌球蛋白的组成， 量（天然凝胶，单克隆抗体放射免疫测定，和 ATP酶活性）和解剖分布（免疫荧光与 单克隆抗体）。

Myosin is a major contractile protein involved in the generation of mechanical force and shortening of cardiac muscle fibers. Multiple isomeric forms of cardiac myosin exist, each exhibiting characteristic biochemical and mechanical properties. The isomyosin composition is responsive to a number of physiologic and pathologic factors including developmental stage, thyroid hormone, and ventricular loading. However, this relationship between the isomyosin composition and the intrinsic mechanical and metabolic properties of the intact left ventricle is unknown. Additionally, it is not known whether the changes in isomyosin composition represent a process of physiologic adaptation at the intact organ level and whether this adaptation becomes inadequate for a certain combination of cardio-circulatory conditions (i.e., end-diastolic volume, arterial load, and heart rate), leading to functional failure of the left ventricle. Accordingly, the two major goals of this proposal are: i) to examine the relationship between changes in isomyosin composition and the intrinsic mechanical and metabolic properties of the left ventricle; and ii) to assess the effects of changing isomyosin composition on the overall performance of the left ventricle. In order to establish whether there exists a 'unique' relationship (i.e., independent of the inciting stimulus) between changes in isomyosin composition and the mechanical and metabolic properties of the left ventricle, several animal models will be examined; hypo- and hyper-thyroidism (rats and rabbits); and pressure-overload (aortic banding in rabbits and spontaneous hypertension in rats). Furthermore, in order to dissect the effects of hypertrophy alone from those due to the variations in isomyosin composition, the pressure-overload models will be further studied with isomyosin composition held constant by concomitant manipulation of thyroid hormone status. The mechanical properties (systolic elastance and resistance) will be assessed both in-situ and in an isolated heart preparation. The metabolic properties will be quantified in isolated heart studies by relating myocardial oxygen consumption to external mechanical work and to systolic pressure-volume area. Isomyosin composition will be analysed both in terms of relative amounts (native-gel, radioimmunoassay with monoclonal antibodies, and ATPase activity), and anatomical distribution (immunofluorescence with monoclonal antibodies).