ROCK1 plays an essential role in the transition from cardiac hypertrophy to failure in mice.
ROCK1 plays an essential role in the transition from cardiac hypertrophy to failure in mice.
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DOI：
10.1016/j.yjmcc.2010.08.008
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发表时间：
2010-11
影响因子：
5
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Shi J;Zhang YW;Yang Y;Zhang L;Wei L
由多种病因引起的病理性心脏肥大最终导致心脏扩张和功能失代偿。我们最近报道了Rho相关卷曲螺旋蛋白激酶1（ROCK 1）的基因缺失抑制了代偿性肥大心脏的几种病理事件，包括心肌细胞凋亡。本研究调查了ROCK 1缺乏是否可以阻止从肥大到心力衰竭的转变。心脏限制性过表达G α q的转基因小鼠在年轻时发生代偿性心肌肥大，但在妊娠后或老年时发展为致命性心肌病，并伴有细胞凋亡增加。这些研究首先使用年龄和妊娠匹配的野生型（WT），G α q，ROCK1 −/−和G α q/ROCK1 −/−小鼠进行。ROCK 1缺失的有效有益作用通过消除围产期死亡率以及显著减弱围产期G α q转基因小鼠的左心室（LV）扩张、室壁变薄和收缩功能障碍得到证实。心肌细胞凋亡的增加受到ROCK1缺失的抑制，与细胞外信号调节激酶/丝裂原活化蛋白激酶（ERK/MAPK）激活的增加和Bax的线粒体易位的抑制有关。此外，ROCK 1缺陷还改善了12个月龄的老年G α q小鼠的存活率，抑制了心肌细胞凋亡，并保留了LV尺寸和功能。此外，在没有妊娠应激的情况下，ROCK 1的转基因过表达增加了G α q心脏中的心肌细胞凋亡并加速了肥大失代偿。本研究首次提供了ROCK1缺乏对肥厚性失代偿的长期有益作用的体内证据，并表明ROCK1可能是限制心力衰竭进展的有吸引力的治疗靶点。
Pathological cardiac hypertrophy caused by diverse etiologies eventually leads to cardiac dilation and functional decompensation. We have recently reported that genetic deletion of Rho-associated coiled-coil containing protein kinase 1 (ROCK1) inhibited several pathological events including cardiomyocyte apoptosis in compensated hypertrophic hearts. The present study investigated whether ROCK1 deficiency can prevent the transition from hypertrophy to heart failure. Transgenic mice with cardiac-restricted overexpression of Gαq develop compensated cardiac hypertrophy at young ages, but progress into lethal cardiomyopathy accompanied by increased apoptosis after pregnancy or at old ages. The studies were first carried out using age- and pregnancy-matched wild-type (WT), Gαq, ROCK1−/−, and Gαq/ROCK1−/− mice. The potent beneficial effect of ROCK1 deletion is demonstrated by abolishment of peripartum mortality, and significant attenuation of left ventricular (LV) dilation, wall thinning, and contractile dysfunction in the peripartum Gαq transgenic mice. Increase in cardiomyocyte apoptosis was suppressed by ROCK1 deletion, associated with increased extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) activation and inhibition of mitochondrial translocation of Bax. In addition, ROCK1 deficiency also improved survival, inhibited cardiomyocyte apoptosis, and preserved LV dimension and function in old Gαq mice at 12 months. Furthermore, transgenic overexpression of ROCK1 increased cardiomyocyte apoptosis and accelerated hypertrophic decompensation in Gαq hearts in the absence of pregnancy stress. The present study provides for the first time in vivo evidence for the long-term beneficial effects of ROCK1 deficiency in hypertrophic decompensation and suggests that ROCK1 may be an attractive therapeutic target to limit heart failure progression.
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影响因子：
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作者：
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通讯作者：
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DOI：
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发表时间：
2007-08-28
影响因子：
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作者：
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