Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure.
Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure.
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MYC介导的肥厚性心肌病和心力衰竭中的细胞周期再进入和线粒体缺陷。
DOI：
10.1371/journal.pone.0007172
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发表时间：
2009-09-25
期刊：
影响因子：
3.7
通讯作者：
Smith MA
中科院分区：
文献类型：
--
作者：
Lee HG;Chen Q;Wolfram JA;Richardson SL;Liner A;Siedlak SL;Zhu X;Ziats NP;Fujioka H;Felsher DW;Castellani RJ;Valencik ML;McDonald JA;Hoit BD;Lesnefsky EJ;Smith MA
虽然相当多的证据支持c-Myc （Myc）增加与心肌病之间的因果关系，作为“胎儿再表达”模式的一部分，但Myc在心肌病机制中的功能作用仍不清楚。为了解决这个问题，我们开发了一种双转基因小鼠，在心肌细胞特异性MHC启动子的控制下诱导表达Myc。在成年小鼠中，心肌细胞中Myc表达的诱导导致严重肥厚性心肌病的发展，随后是心室功能障碍，最终死于充血性心力衰竭。在机制上，Myc激活后，细胞周期标记物和其他DNA复制指标显著增加，提示细胞周期相关事件可能是心功能障碍的主要机制。此外，细胞水平的病理改变包括线粒体功能的改变，线粒体生物发生失调和电子传递链复合物I和III的缺陷。这些数据与Myc在包括细胞周期激活、线粒体增殖和凋亡在内的几种不同途径中的已知作用一致，并表明Myc在心肌细胞中的激活是下游病理后遗症的重要调节因子。此外，我们的研究结果表明，Myc在心肌细胞中的诱导足以引起心肌病和心力衰竭，而Myc的持续诱导，导致成人心肌细胞的细胞周期重新进入，代表了成熟心脏的适应性不良反应。
While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a “fetal re-expression” pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.
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DOI：
10.1073/pnas.85.2.339
发表时间：
1988-01-01
影响因子：
11.1
作者：
IZUMO, S;NADALGINARD, B;MAHDAVI, V
通讯作者：
MAHDAVI, V
DOI：
10.1152/ajpheart.1997.273.3.h1544
发表时间：
1997-09-01
影响因子：
4.8
作者：
Lesnefsky, EJ;Tandler, B;Hoppel, CL
通讯作者：
Hoppel, CL
DOI：
10.1152/ajpheart.00816.2006
发表时间：
2007-05-01
影响因子：
4.8
作者：
Barrick, Cordelia J.;Rojas, Mauricio;Threadgill, David W.
通讯作者：
Threadgill, David W.
DOI：
10.1152/ajpheart.00619.2002
发表时间：
2003-02-01
影响因子：
4.8
作者：
Lucas, DT;Aryal, P;Leinwand, LA
通讯作者：
Leinwand, LA
影响因子：
6
作者：
Cash, AD;Aliev, G;Perry, G
通讯作者：
Perry, G