A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium.
A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium.
复制标题
DOI：
10.3389/fphys.2014.00363
复制
发表时间：
2014
影响因子：
4
通讯作者：
Baker AJ
中科院分区：
文献类型：
--
作者：
Lovett DH;Chu C;Wang G;Ratcliffe MB;Baker AJ
基质金属蛋白酶-2（FL-MMP-2）的全长亚型在心脏细胞外基质的转换中起作用。FL-MMP-2也存在于细胞内，与肌节相关，并且在氧化应激的情况下，切割肌丝蛋白，导致收缩力受损。最近，一种新的N-末端截短的MMP-2亚型（NTT-MMP-2）在氧化应激过程中产生的鉴定和显示，诱导严重的收缩功能衰竭，但是，损伤机制仍不清楚。在这项研究中，心脏特异性NTT-MMP-2转基因小鼠被用来确定NTT-MMP-2的生理作用：完整心肌的力发展;心肌肌丝在去膜心肌的功能;和在分离的肌细胞内Ca 2+瞬变。我们将NTT-MMP-2表达引起的收缩缺陷与使用免疫组织化学确定的NTT-MMP-2的已知细胞内位置相关。与心脏特异性FL-MMP-2转基因小鼠产生的病理生理学进行比较。与以前的研究一致，FL-MMP-2定位于肌丝，而NTT-MMP-2集中在肌膜下线粒体和与Z线配准的位点。NTT-MMP-2表达导致完整心肌的力发展减少50%。然而，NTT-MMP-2的表达并没有减少肌丝力的发展，与NTT-MMP-2缺乏肌丝定位一致。NTT-MMP-2表达导致Ca 2+瞬变幅度降低50%，表明活化受损。结论：NTT-MMP-2与FL-MMP-2不同，不介导肌丝损伤。相反，NTT-MMP-2导致受损的肌细胞活化，这可能涉及由于线粒体中的定位和/或影响Ca 2+瞬变的横小管的影响。因此，FL-MMP-2和NTT-MMP-2具有离散的细胞内位置并介导对心肌细胞的不同细胞内损伤。
The full-length isoform of matrixmetalloproteinase-2 (FL-MMP-2) plays a role in turnover of the cardiac extracellular matrix. FL-MMP-2 is also present intracellularly in association with sarcomeres and, in the setting of oxidative stress, cleaves myofilament proteins with resultant impaired contractility. Recently, a novel N-terminal truncated MMP-2 isoform (NTT-MMP-2) generated during oxidative stress was identified and shown to induce severe systolic failure; however, the injury mechanisms remained unclear. In this study, cardiac-specific NTT-MMP-2 transgenic mice were used to determine the physiological effects of NTT-MMP-2 on: force development of intact myocardium; the function of cardiac myofilaments in demembranated myocardium; and on intracellular Ca2+ transients in isolated myocytes. We related the contractile defects arising from NTT-MMP-2 expression to the known intracellular locations of NTT-MMP-2 determined using immunohistochemistry. Comparison was made with the pathophysiology arising from cardiac-specific FL-MMP-2 transgenic mice. Consistent with previous studies, FL-MMP-2 was localized to myofilaments, while NTT-MMP-2 was concentrated within subsarcolemmal mitochondria and to sites in register with the Z-line. NTT-MMP-2 expression caused a 50% reduction of force development by intact myocardium. However, NTT-MMP-2 expression did not reduce myofilament force development, consistent with the lack of NTT-MMP-2 localization to myofilaments. NTT-MMP-2 expression caused a 50% reduction in the amplitude of Ca2+ transients, indicating impaired activation. Conclusions: Unlike FL-MMP-2, NTT-MMP-2 does not mediate myofilament damage. Instead, NTT-MMP-2 causes impaired myocyte activation, which may involve effects due to localization in mitochondria and/or to transverse tubules affecting Ca2+ transients. Thus, FL-MMP-2 and NTT-MMP-2 have discrete intracellular locations and mediate different intracellular damage to cardiac myocytes.
登录
查看更多内容
DOI：
10.1152/ajpheart.00207.2003
发表时间：
2003-09-01
影响因子：
4.8
作者：
Hayashidani, S;Tsutsui, H;Takeshita, A
通讯作者：
Takeshita, A
影响因子：
37.8
作者：
Sawicki, G;Leon, H;Schulz, R
通讯作者：
Schulz, R
影响因子：
2.7
作者：
Cannell, M. B.;Crossman, D. J.;Soeller, C.
通讯作者：
Soeller, C.
影响因子：
2.6
作者：
Cogni, Ana Lucia;Farah, Elaine;Zornoff, Leonardo A. M.
通讯作者：
Zornoff, Leonardo A. M.
DOI：
10.1152/ajpheart.01343.2005
发表时间：
2006-11-01
影响因子：
4.8
作者：
Mukherjee, Rupak;Mingoia, Joseph T.;Spinale, Francis G.
通讯作者：
Spinale, Francis G.