Hypertrophic cardiomyopathy associated Lys104Glu mutation in the myosin regulatory light chain causes diastolic disturbance in mice.
Hypertrophic cardiomyopathy associated Lys104Glu mutation in the myosin regulatory light chain causes diastolic disturbance in mice.
复制标题
DOI：
10.1016/j.yjmcc.2014.06.011
复制
发表时间：
2014-09
影响因子：
5
通讯作者：
Szczesna-Cordary, Danuta
中科院分区：
文献类型：
--
作者：
Huang, Wenrui;Liang, Jingsheng;Kazmierczak, Katarzyna;Muthu, Priya;Duggal, Divya;Farman, Gerrie P.;Sorensen, Lars;Pozios, Iraklis;Abraham, Theodore P.;Moore, Jeffrey R.;Borejdo, Julian;Szczesna-Cordary, Danuta
关键词：
我们首次研究了家族性肥厚型心肌病 (HCM) 相关的肌球蛋白调节轻链 (RLC) 中 Lys104Glu 突变的影响。生成表达 Lys104Glu 取代 (Tg-MUT) 的转基因小鼠，并将结果与 Tg-WT（野生型人心室 RLC）小鼠进行比较。 6 个月大的 Tg-MUT 的脉冲波多普勒超声心动图显示舒张期紊乱的早期迹象，E/A 传输速度比显着降低。 6 个月大的 Tg-MUT 小鼠的侵入性血流动力学也显示出等容舒张时间 (Tau) 显着延长和压力下降速度较慢的趋势，表明 Tg-MUT 的舒张功能发生了变化。六个月大的突变动物没有左心室肥厚；然而，在>13个月时，它们表现出明显的肥大和纤维化。在 5-6 个月大小鼠的去皮乳头肌中，观察到突变导致最大张力降低和肌肉松弛率减慢。突变的跨桥显示出与细丝的结合率增加，并且动力冲程的速度更快。此外，与 Tg-WT 相比，在突变体中观察到 RLC 磷酸化水平降低约 2 倍。与 Tg-MUT 心脏中线粒体含量较高一致，MUT 肌球蛋白 ATP 酶活性显着高于 WT 肌球蛋白，表明能量消耗增加。在体外运动测定中，MUT 肌球蛋白在零负载下产生更高的肌动蛋白滑动速度，但与 WT 肌球蛋白相比，MUT 的速度随着施加负载而急剧下降。我们的结果表明，舒张功能障碍（肌肉松弛受损、E/A 降低）和能量使用效率低下（收缩力降低和 ATP 消耗加快）可能是 Lys104Glu 介导的 HCM 表型的基础。
We have examined, for the first time, the effects of the familial hypertrophic cardiomyopathy (HCM)- associated Lys104Glu mutation in the myosin regulatory light chain (RLC). Transgenic mice expressing the Lys104Glu substitution (Tg-MUT) were generated and the results compared to Tg-WT (wild-type human ventricular RLC) mice. Echocardiography with pulse wave Doppler in 6 month-old Tg-MUT showed early signs of diastolic disturbance with significantly reduced E/A transmitral velocities ratio. Invasive hemodynamics in 6 month-old Tg-MUT mice also demonstrated a borderline significant prolonged isovolumic relaxation time (Tau) and a tendency for slower rate of pressure decline, suggesting alterations in diastolic function in Tg-MUT. Six month-old mutant animals had no LV hypertrophy; however, at >13 months they displayed significant hypertrophy and fibrosis. In skinned papillary muscles from 5-6 month-old mice a mutation induced reduction in maximal tension and slower muscle relaxation rates were observed. Mutated cross-bridges showed increased rates of binding to the thin filaments and a faster rate of the power stroke. In addition, ~2-fold lower level of RLC phosphorylation was observed in the mutant compared to Tg-WT. In line with the higher mitochondrial content seen in Tg-MUT hearts, the MUT-myosin ATPase activity was significantly higher than WT-myosin, indicating increased energy consumption. In the in vitro motility assay, MUT-myosin produced higher actin sliding velocity under zero load, but the velocity drastically decreased with applied load in the MUT vs. WT myosin. Our results suggest that diastolic disturbance (impaired muscle relaxation, lower E/A) and inefficiency of energy use (reduced contractile force and faster ATP consumption) may underlie the Lys104Glu-mediated HCM phenotype.
登录
查看更多内容
影响因子：
--
作者：
Santos S;Marques V;Pires M;Silveira L;Oliveira H;Lança V;Brito D;Madeira H;Esteves JF;Freitas A;Carreira IM;Gaspar IM;Monteiro C;Fernandes AR
通讯作者：
Fernandes AR
影响因子：
120.7
作者：
Redfield, MM;Jacobsen, SJ;Rodeheffer, RJ
通讯作者：
Rodeheffer, RJ
影响因子：
14
作者：
Afonso, Luis C.;Bernal, Juan;Abraham, Theodore P.
通讯作者：
Abraham, Theodore P.
DOI：
10.1023/a:1017903709361
发表时间：
2002-02-01
期刊：
Cardiac electrophysiology review
影响因子：
--
作者：
Maron, Barry J
通讯作者：
Maron, Barry J
影响因子：
3.9
作者：
Andersen, Paal Skytt;Havndrup, Ole;Bundgaard, Henning
通讯作者：
Bundgaard, Henning