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Calcium-independent negative inotropy by beta-myosin heavy chain gene transfer in cardiac myocytes.
Circulation Research ( IF 20.1 ) Pub Date : 2007-03-17 , DOI: 10.1161/01.res.0000264102.00706.4e
Todd J Herron 1 , Rene Vandenboom , Ekaterina Fomicheva , Lakshmi Mundada , Terri Edwards , Joseph M Metzger
Affiliation  

Increased relative expression of the slow molecular motor of the heart (beta-myosin heavy chain [MyHC]) is well known to occur in many rodent models of cardiovascular disease and in human heart failure. The direct effect of increased relative beta-MyHC expression on intact cardiac myocyte contractility, however, is unclear. To determine the direct effects of increased relative beta-MyHC expression on cardiac contractility, we used acute genetic engineering with a recombinant adenoviral vector (AdMYH7) to genetically titrate beta-MyHC protein expression in isolated rodent ventricular cardiac myocytes that predominantly expressed alpha-MyHC (fast molecular motor). AdMYH7-directed beta-MyHC protein expression and sarcomeric incorporation was observed as soon as 1 day after gene transfer. Effects of beta-MyHC expression on myocyte contractility were determined in electrically paced single myocytes (0.2 Hz, 37 degrees C) by measuring sarcomere shortening and intracellular calcium cycling. Gene transfer-based replacement of alpha-MyHC with beta-MyHC attenuated contractility in a dose-dependent manner, whereas calcium transients were unaffected. For example, when beta-MyHC expression accounted for approximately 18% of the total sarcomeric myosin, the amplitude of sarcomere-length shortening (nanometers, nm) was depressed by 42% (151.0+/-10.7 [control] versus 87.0+/-5.4 nm [AdMYH7 transduced]); and genetic titration of beta-MyHC, leading to 38% beta-MyHC content, attenuated shortening by 57% (138.9+/-13.0 versus 59.7+/-7.1 nm). Maximal isometric cross-bridge cycling rate was also slower in AdMYH7-transduced myocytes. Results indicate that small increases of beta-MyHC expression (18%) have Ca2+ transient-independent physiologically relevant effects to decrease intact cardiac myocyte function. We conclude that beta-MyHC is a negative inotrope among the cardiac myofilament proteins.

中文翻译:

β-肌球蛋白重链基因转移在心肌细胞中的钙非依赖性负性肌力。

众所周知,在许多心血管疾病的啮齿动物模型和人类心力衰竭中,心脏慢分子运动(β-肌球蛋白重链[MyHC])的相对表达增加。但是,尚不清楚相对β-MyHC相对表达的增加对完整心肌细胞收缩力的直接影响。为了确定相对β-MyHC表达增加对心脏收缩力的直接影响,我们使用了带有重组腺病毒载体(AdMYH7)的急性基因工程技术,以基因滴定了主要表达α-MyHC(快速分子马达)。基因转移后第1天即可观察到AdMYH7指导的β-MyHC蛋白表达和肌节掺入。通过测量肌节缩短和细胞内钙循环,确定电起搏的单个心肌细胞(0.2 Hz,37摄氏度)中β-MyHC表达对心肌细胞收缩力的影响。基于基因转移的β-MyHC替代α-MyHC以剂量依赖性方式减弱了收缩力,而钙瞬变则不受影响。例如,当β-MyHC表达约占肌节肌球蛋白总量的18%时,肌节长度缩短的幅度(纳米,nm)降低了42%(151.0 +/- 10.7 [对照]对87.0 +/- 5.4 nm [AdMYH7转导]);β-MyHC的基因滴定和基因滴定(导致38%的β-MyHC含量)缩短了57%(138.9 +/- 13.0对59.7 +/- 7.1 nm)。在AdMYH7转导的心肌细胞中,最大等距跨桥循环速率也较慢。结果表明,β-MyHC表达的少量增加(18%)具有与Ca2 +无关的生理相关效应,以降低完整的心肌细胞功能。我们得出结论,β-MyHC是心肌肌丝蛋白中的负性肌力体。
更新日期:2019-11-01
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