Microtubule Actin Cross-linking Factor 1 regulates cardiomyocyte microtubule distribution and adaptation to hemodynamic overload.
Microtubule Actin Cross-linking Factor 1 regulates cardiomyocyte microtubule distribution and adaptation to hemodynamic overload.
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DOI：
10.1371/journal.pone.0073887
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Fassett JT;Xu X;Kwak D;Wang H;Liu X;Hu X;Bache RJ;Chen Y
异常的心肌细胞微管生长是压力超负荷诱导的心脏肥大的特征，被认为有助于左心室（LV）功能障碍。微管肌动蛋白交联因子1（MACF 1/Acf 7）是一种600 kd的谱斑蛋白，其稳定并引导微管沿沿着生长。MACF 1在心脏中表达，但其对心脏微管的影响，以及这如何影响心脏结构，功能和对血流动力学过载的适应尚不清楚。在此，我们使用可诱导的心脏特异性MACF 1敲除小鼠（MACF 1 KO）来确定MACF 1对心脏微管和对压力超负荷（横主动脉收缩（TAC））的适应的影响。在成年小鼠心脏中，MACF 1表达在基础条件下较低，但在对TAC的反应中显著增加。虽然MACF 1 KO在基础条件下对心脏大小或功能没有可观察到的影响，但MACF 1 KO加重了TAC诱导的LV肥大、LV扩张和收缩功能障碍。有趣的是，心室裂解物的亚细胞分级显示，MACF 1 KO改变微管分布响应于TAC，使更多的微管蛋白与细胞膜部分。此外，TAC在WT和MACF 1 KO小鼠中诱导微管重新分布到该细胞膜部分中与收缩功能障碍的水平显著相关（r2 = 0.786，p<.001）。 MACF 1破坏也导致TAC后膜小窝蛋白3水平降低，膜PKCα和β1整合素水平升高，表明MACF 1功能对肥大期间几种生理相关信号蛋白的空间调节很重要。总之，这些数据首次确定了MACF 1在心肌细胞微管分布和适应血流动力学过载中的作用。
Aberrant cardiomyocyte microtubule growth is a feature of pressure overload induced cardiac hypertrophy believed to contribute to left ventricular (LV) dysfunction. Microtubule Actin Cross-linking Factor 1 (MACF1/Acf7) is a 600 kd spectraplakin that stabilizes and guides microtubule growth along actin filaments. MACF1 is expressed in the heart, but its impact on cardiac microtubules, and how this influences cardiac structure, function, and adaptation to hemodynamic overload is unknown. Here we used inducible cardiac-specific MACF1 knockout mice (MACF1 KO) to determine the impact of MACF1 on cardiac microtubules and adaptation to pressure overload (transverse aortic constriction (TAC).In adult mouse hearts, MACF1 expression was low under basal conditions, but increased significantly in response to TAC. While MACF1 KO had no observable effect on heart size or function under basal conditions, MACF1 KO exacerbated TAC induced LV hypertrophy, LV dilation and contractile dysfunction. Interestingly, subcellular fractionation of ventricular lysates revealed that MACF1 KO altered microtubule distribution in response to TAC, so that more tubulin was associated with the cell membrane fraction. Moreover, TAC induced microtubule redistribution into this cell membrane fraction in both WT and MACF1 KO mice correlated strikingly with the level of contractile dysfunction (r2 = 0.786, p<.001). MACF1 disruption also resulted in reduction of membrane caveolin 3 levels, and increased levels of membrane PKCα and β1 integrin after TAC, suggesting MACF1 function is important for spatial regulation of several physiologically relevant signaling proteins during hypertrophy. Together, these data identify for the first time, a role for MACF1 in cardiomyocyte microtubule distribution and in adaptation to hemodynamic overload.
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影响因子：
20.1
作者：
Iribe G;Ward CW;Camelliti P;Bollensdorff C;Mason F;Burton RA;Garny A;Morphew MK;Hoenger A;Lederer WJ;Kohl P
通讯作者：
Kohl P
DOI：
10.1152/ajpheart.00462.2009
发表时间：
2009-08-01
影响因子：
4.8
作者：
Fassett, John T.;Xu, Xin;Bache, Robert J.
通讯作者：
Bache, Robert J.
DOI：
10.1083/jcb.149.1.195
发表时间：
2000-04-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Karakesisoglou I;Yang Y;Fuchs E
通讯作者：
Fuchs E
影响因子：
20.1
作者：
Sohal, DS;Nghiem, M;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
10.8
作者：
Nakamura, Y;Miura, T;Shimamoto, K
通讯作者：
Shimamoto, K