Herron Todd J, Devaney Eric J, Metzger Joseph M
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Ann N Y Acad Sci. 2008 Mar;1123:96-104. doi: 10.1196/annals.1420.011.
Cardiac muscle performance can be determined by factors intrinsic to each cardiac muscle cell, such as protein isoform expression. One protein whose expression plays a major role in determining cardiac performance is myosin. Myosin is the heart's molecular motor which transduces the chemical energy from ATP hydrolysis into the mechanical energy of each heartbeat. Alterations of myosin isoform expression are routinely associated with acquired and inherited cases of cardiomyopathy. For example, human heart failure is consistently associated with increased expression of a slow myosin motor isoform and a concomitant decreased expression of the heart's fast myosin motor isoform. Further, mutations of the cardiac myosin gene are the most common cause of inherited hypertrophic cardiomyopathy. Transgenic animal studies have provided insight into cardiac functional effects caused by myosin isoform gene switching (fast-to-slow myosin or slow-to-fast myosin) or by expression of a disease-related mutant motor. More direct structure-function analysis using acute gene transfer of myosin motors provides evidence that the inotropic state of cardiac muscle can be affected by motor protein isoform shifting independent of intracellular calcium handling. Because most therapies for the diseased heart target intracellular calcium handling, acute gene transfer of cardiac molecular motors to modulate heart performance offers a novel therapeutic strategy for the compromised heart. Although the development of safe vectors for therapeutic myosin gene delivery are in their infancy, studies focused on acute genetic engineering of the heart's molecular motor will provide a foundation for therapeutic vector development and insight into mechanisms that contribute to cardiomyopathy.
心肌性能可由每个心肌细胞的内在因素决定，如蛋白质异构体表达。其中一种表达在决定心脏性能中起主要作用的蛋白质是肌球蛋白。肌球蛋白是心脏的分子马达，它将ATP水解产生的化学能转化为每次心跳的机械能。肌球蛋白异构体表达的改变通常与获得性和遗传性心肌病病例相关。例如，人类心力衰竭一直与慢肌球蛋白马达异构体表达增加以及心脏快肌球蛋白马达异构体表达相应减少有关。此外，心肌肌球蛋白基因的突变是遗传性肥厚型心肌病的最常见原因。转基因动物研究为肌球蛋白异构体基因转换（快肌球蛋白向慢肌球蛋白或慢肌球蛋白向快肌球蛋白）或疾病相关突变马达的表达所引起的心脏功能效应提供了见解。使用肌球蛋白马达的急性基因转移进行的更直接的结构-功能分析提供了证据，表明心肌的变力状态可受马达蛋白异构体转换的影响，而与细胞内钙处理无关。由于大多数针对患病心脏的治疗方法都以细胞内钙处理为靶点，通过急性基因转移心脏分子马达来调节心脏性能为受损心脏提供了一种新的治疗策略。尽管用于治疗性肌球蛋白基因递送的安全载体的开发尚处于起步阶段，但专注于心脏分子马达急性基因工程的研究将为治疗性载体的开发以及对导致心肌病的机制的深入了解奠定基础。
