Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI
Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI
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DOI：
10.1152/ajpheart.91506.2007
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发表时间：
2008-06-01
影响因子：
4.8
通讯作者：
Huang, Xu-Pei
中科院分区：
文献类型：
--
作者：
Du, Jianfeng;Liu, Jing;Huang, Xu-Pei
产生的转基因小鼠在心脏中表达限制性心肌病 (RCM) 人心肌肌钙蛋白 I (cTnI) R192H 突变（cTnI(193His) 小鼠）。本研究的目的是评估舒张功能障碍发展过程中的心脏功能，并深入了解 RCM cTnI 突变的病理生理影响。对 cTnI193His 小鼠和野生型同窝小鼠的心脏功能和病理生理变化进行为期 12 个月的监测。它从异常松弛逐渐进展为舒张功能障碍，其特征是高分辨率超声心动图表现为E-A比反转、减速时间增加和等容舒张时间延长。 12月龄时，cTnI193His小鼠心输出量明显下降，部分转基因小鼠出现充血性心力衰竭。 cTnI193His 对心室收缩和舒张的负面影响在离体小鼠工作心脏制剂中得到进一步证明。 cTnI193His 肌细胞的主要形态变化是细胞长度缩短。多巴酚丁胺刺激可增加 cTnI193His 小鼠的心率，但不能改善 CO。cTnI193His 小鼠的表型与携带 cTnI 突变的人类 RCM 患者相似，其形态学特征为心房扩大和心室受限，功能上表现为舒张功能障碍和舒张性心力衰竭。结果表明 cTnI 的 COOH 末端结构域在心肌舒张功能中发挥着关键作用。
Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart (cTnI(193His) mice). The objective of this study was to assess cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function and pathophysiological changes were monitored in cTnI193His mice and wild-type littermates for a period of 12 mo. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with high-resolution echocardiography by a reversed E-to-A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. At the age of 12 mo, cardiac output in cTnI193His mice was significantly declined, and some transgenic mice showed congestive heart failure. The negative impact of cTnI193His on ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. The main morphological change in cTnI193His myocytes was shortened cell length. Dobutamine stimulation increased heart rate in cTnI193His mice but did not improve CO. The cTnI193His mice had a phenotype similar to that in human RCM patients carrying the cTnI mutation characterized morphologically by enlarged atria and restricted ventricles and functionally by diastolic dysfunction and diastolic heart failure. The results demonstrate a critical role of the COOH-terminal domain of cTnI in the diastolic function of cardiac muscle.