Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity
Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity
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DOI：
10.1161/circresaha.107.148379
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发表时间：
2007-07-20
影响因子：
20.1
通讯作者：
Wieczorek, David F.
中科院分区：
文献类型：
--
作者：
Rajan, Sudarsan;Ahmed, Rafeeq P. H.;Wieczorek, David F.
横纹肌α-原肌球蛋白（α-TM）是一种必需的细丝蛋白，其突变可引起扩张型心肌病（DCM）和家族性肥厚型心肌病。α-原肌球蛋白中的两个不同的点突变与人类DCM的发展相关：Glu 40 Lys和Glu 54 Lys。为了研究与DCM相关的α-TM突变的功能后果，我们产生了在成年心脏中表达突变体α-TM（Glu 54 Lys）的转基因小鼠。结果表明，转基因蛋白表达的增加导致内源性α-TM水平的相互降低，总肌丝TM蛋白水平保持不变。组织学和形态学分析显示DCM发展为心力衰竭，6个月时经常死亡。超声心动图分析证实了心脏的扩张表型，左心室缩短率显著降低。工作执行的心脏分析表明，心脏收缩和舒张功能显着受损，心肌纤维的力测量显示，肌丝有显着降低Ca 2+的敏感性和张力的产生。实时RT-PCR定量显示β-肌球蛋白重链、脑利钠肽和骨骼肌动蛋白的表达增加，钙处理蛋白肌浆网Ca 2 +-ATP酶和ryanodine受体的表达减少。此外，我们的研究还表明，α-TM 54突变降低原肌球蛋白的灵活性，这可能会影响肌动蛋白结合和肌丝Ca 2+的敏感性。这些小鼠表现出的病理和生理表型与在人DCM和心力衰竭中观察到的那些一致。因此，这是第一个肌节细丝蛋白（特别是TM）突变导致DCM的小鼠模型。
Mutations in striated muscle alpha-tropomyosin (alpha-TM), an essential thin filament protein, cause both dilated cardiomyopathy ( DCM) and familial hypertrophic cardiomyopathy. Two distinct point mutations within alpha-tropomyosin are associated with the development of DCM in humans: Glu40Lys and Glu54Lys. To investigate the functional consequences of alpha-TM mutations associated with DCM, we generated transgenic mice that express mutant alpha-TM ( Glu54Lys) in the adult heart. Results showed that an increase in transgenic protein expression led to a reciprocal decrease in endogenous alpha-TM levels, with total myofilament TM protein levels remaining unaltered. Histological and morphological analyses revealed development of DCM with progression to heart failure and frequently death by 6 months. Echocardiographic analyses confirmed the dilated phenotype of the heart with a significant decrease in the left ventricular fractional shortening. Work-performing heart analyses showed significantly impaired systolic, and diastolic functions and the force measurements of cardiac myofibers revealed that the myofilaments had significantly decreased Ca2+ sensitivity and tension generation. Real-time RT-PCR quantification demonstrated an increased expression of beta-myosin heavy chain, brain natriuretic peptide, and skeletal actin and a decreased expression of the Ca2+ handling proteins sarcoplasmic reticulum Ca2+-ATPase and ryanodine receptor. Furthermore, our study also indicates that the alpha-TM54 mutation decreases tropomyosin flexibility, which may influence actin binding and myofilament Ca2+ sensitivity. The pathological and physiological phenotypes exhibited by these mice are consistent with those seen in human DCM and heart failure. As such, this is the first mouse model in which a mutation in a sarcomeric thin filament protein, specifically TM, leads to DCM.