Fewell J G, Hewett T E, Sanbe A, Klevitsky R, Hayes E, Warshaw D, Maughan D, Robbins J
Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA.
J Clin Invest. 1998 Jun 15;101(12):2630-9. doi: 10.1172/JCI2825.
The different functions of the ventricular- and atrial-specific essential myosin light chains are unknown. Using transgenesis, cardiac-specific overexpression of proteins can be accomplished. The transgenic paradigm is more useful than originally expected, in that the mammalian heart rigorously controls sarcomeric protein stoichiometries. In a clinical subpopulation suffering from heart disease caused by congenital malformations of the outflow tract, an ELC1v-->ELC1a isoform shift correlated with increases in cross-bridge cycling kinetics as measured in skinned fibers derived from the diseased muscle. We have used transgenesis to replace the ventricular isoform of the essential myosin light chain with the atrial isoform. The ELC1v--> ELC1a shift in the ventricle resulted in similar functional alterations. Unloaded velocities as measured by the ability of the myosin to translocate actin filaments in the in vitro motility assay were significantly increased as a result of the isoform substitution. Unloaded shortening velocity was also increased in skinned muscle fibers, and at the whole organ level, both contractility and relaxation were significantly increased. This increase in cardiac function occurred in the absence of a hypertrophic response. Thus, ELC1a expression in the ventricle appears to be advantageous to the heart, resulting in increased cardiac function.
心室和心房特异性必需肌球蛋白轻链的不同功能尚不清楚。利用转基因技术，可以实现蛋白质在心脏中的特异性过表达。转基因模式比最初预期的更有用，因为哺乳动物心脏严格控制肌节蛋白的化学计量。在一个因流出道先天性畸形导致心脏病的临床亚群中，ELC1v到ELC1a异构体的转变与在患病肌肉的去表皮纤维中测量的横桥循环动力学增加相关。我们利用转基因技术将必需肌球蛋白轻链的心室异构体替换为心房异构体。心室中ELC1v到ELC1a的转变导致了类似的功能改变。在体外运动分析中，通过肌球蛋白移动肌动蛋白丝的能力测量的空载速度由于异构体替代而显著增加。去表皮肌纤维中的空载缩短速度也增加了，在整个器官水平上，收缩性和舒张性都显著增加。心脏功能的这种增加发生在没有肥大反应的情况下。因此，心室中ELC1a的表达似乎对心脏有利，导致心脏功能增强。
