Extensible behavior of titin in the miniswine left ventricle.
Extensible behavior of titin in the miniswine left ventricle.
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DOI：
10.1161/circulationaha.109.918151
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发表时间：
2010-02-16
期刊：
影响因子：
37.8
通讯作者：
Granzier H
中科院分区：
文献类型：
--
作者：
Lewinter MM;Popper J;McNabb M;Nyland L;Bell SB;Granzier H
肌节蛋白Titin是一种分子弹簧，负责心肌细胞的被动张力和恢复力。已经在啮齿动物中研究了肌动蛋白的延伸与肌节长度(SL)的函数关系，啮齿动物主要表达更小、更硬的N2B肌动蛋白亚型。大型哺乳动物共表达N2B和N2BA的比例大致相同，N2B和N2BA是更大、更顺从的异构体。我们假设，在大型哺乳动物中，Titin相对于SL的延伸是不同的，这种差异在功能上是重要的。我们描述了舒张期停滞小猪左心室的充盈压力(FP)-SL关系。在FP~0μHg时，SL为2.15~2.2 5μm，在充盈时达到最大值~2.5 0 mm。在正常的FP范围内，SL的范围从~2.32到~2.40μm。我们使用免疫电子显微镜评估了Titin延伸作为SL的函数，从而可以描绘特定弹簧节段的行为。主要的异构体差异是N2B中的N2B-us片段作为SL的函数比N2BA-Titin延长了~4倍。利用这一片段，我们用蠕虫链模型估计了肌节力量的发展，发现N2B比N2BA Titin发展的力量明显更大。N2B和N2BA共同表达的合力是中等的。根据小鼠的研究表明，运作中的SLS比小型葡萄酒更短，我们的结果表明，在大型哺乳动物中，两种肌动蛋白亚型的共同表达可以使SLS更长，而不会出现过度的舒张期张力。
The sarcomeric protein titin is a molecular spring responsible for passive tension and restoring forces of cardiomyocytes. Extension of titin as a function of sarcomere length (SL) has been studied in rodents, who predominantly express the smaller, stiffer N2B titin isoform. Large mammals co-express roughly equal proportions of N2B and N2BA titin, the larger, more compliant isoform. We hypothesized that extension of titin in relation to SL differs in large mammals and this difference is functionally important. We characterized the filling pressure (FP)-SL relation in diastolic arrested miniswine LVs. SL was 2.15–2.25 μm at FP ~0 mmHg and reached a maximum of ~2.50 μm with overfilling. Over the normal FP range, SL ranged from ~2.32 to ~2.40 μm. We assessed titin extension as a function of SL using immunoelectron microscopy, which allowed delineation of the behavior of specific spring segments. The major isoform difference was that the N2B-Us segment extended ~4-fold more as a function of SL in N2B compared with N2BA titin. Using this segment we estimated sarcomeric force development with a worm-like chain model and found that N2B develops markedly greater force than N2BA titin. The resulting force with co-expression of N2B and N2BA titin is intermediate. In light of murine studies showing that operating SLs are shorter than in miniswine, our results indicate that co-expression of the two titin isoforms in large mammals allows longer SLs without development of excessive diastolic tension.