Truncation of titin's elastic PEVK region leads to cardiomyopathy with diastolic dysfunction.
Truncation of titin's elastic PEVK region leads to cardiomyopathy with diastolic dysfunction.
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DOI：
10.1161/circresaha.109.200964
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发表时间：
2009-09-11
影响因子：
20.1
通讯作者：
Gotthardt M
中科院分区：
文献类型：
--
作者：
Granzier HL;Radke MH;Peng J;Westermann D;Nelson OL;Rost K;King NM;Yu Q;Tschöpe C;McNabb M;Larson DF;Labeit S;Gotthardt M
巨大的蛋白肌联在肌丝组装中发挥关键作用，并决定肌节的被动机械特性。心脏肌联蛋白分子有两个主要的弹性元件，N2B 和 PEVK 区域。两者都被建议用来确定心脏的弹性特性，但功能数据的损失仅适用于 N2B 区域。研究 titin 的 PEVK 区域对生物力学和心脏生长的贡献。我们移除了与 N2B 肌联蛋白（主要心脏肌联蛋白亚型）的 PEVK 元件相对应的 PEVK 片段（外显子 219-225；282aa）的一部分。根据压力-容积环、超声心动图、离体心脏实验和肌肉力学测定，成年纯合 PEVK 敲除 (KO) 小鼠出现舒张功能障碍。免疫电子显微镜显示 N2B 元件的应变增加，N2B 元件是 PEVK-KO 中保留的弹簧区域。有趣的是，PEVK-KO 小鼠的心脏肥大，并诱导肥大和胎儿基因反应，包括 FHL 蛋白上调。这将心脏萎缩表型与 N2B 元件缺失导致的 FHL2 水平降低形成对比。 Titin 的 PEVK 区域有助于心室的弹性。我们的研究结果与 N2B 弹簧元件应变和 FHL 蛋白表达触发心脏肥大的模型一致。这些新发现为未来孤立性舒张功能障碍与更复杂的心肌病的差异化治疗提供了分子基础。
The giant protein titin plays key roles in myofilament assembly and determines the passive mechanical properties of the sarcomere. The cardiac titin molecule has two mayor elastic elements, the N2B and the PEVK region. Both have been suggested to determine the elastic properties of the heart with loss of function data only available for the N2B region. Investigate the contribution of titin’s PEVK region to biomechanics and growth of the heart. We removed a portion of the PEVK segment (exons 219–225; 282aa) that corresponds to the PEVK element of N2B titin, the main cardiac titin isoform. Adult homozygous PEVK knockout (KO) mice developed diastolic dysfunction, as determined by pressure-volume loops, echocardiography, isolated heart experiments, and muscle mechanics. Immunoelectron microscopy revealed increased strain of the N2B element, a spring region retained in the PEVK-KO. Interestingly, the PEVK-KO mice had hypertrophied hearts with an induction of the hypertrophy and fetal gene response that includes upregulation of FHL proteins. This contrasts the cardiac atrophy phenotype with decreased FHL2 levels that result from the deletion of the N2B element. Titin’s PEVK region contributes to the elastic properties of the cardiac ventricle. Our findings are consistent with a model in which strain of the N2B spring element and expression of FHL proteins trigger cardiac hypertrophy. These novel findings provide a molecular basis for the future differential therapy of isolated diastolic dysfunction versus more complex cardiomyopathies.