Xing Weibing, Zhang Tong-Cun, Cao Dongsun, Wang Zhigao, Antos Christopher L, Li Shijie, Wang Yibin, Olson Eric N, Wang Da-Zhi
Carolina Cardiovascular Biology Center, Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599-7126, USA.
Circ Res. 2006 Apr 28;98(8):1089-97. doi: 10.1161/01.RES.0000218781.23144.3e. Epub 2006 Mar 23.
In response to stress signals, postnatal cardiomyocytes undergo hypertrophic growth accompanied by activation of a fetal gene program, assembly of sarcomeres, and cellular enlargement. We show that hypertrophic signals stimulate the expression and transcriptional activity of myocardin, a cardiac and smooth muscle-specific coactivator of serum response factor (SRF). Consistent with a role for myocardin as a transducer of hypertrophic signals, forced expression of myocardin in cardiomyocytes is sufficient to substitute for hypertrophic signals and induce cardiomyocyte hypertrophy and the fetal cardiac gene program. Conversely, a dominant-negative mutant form of myocardin, which retains the ability to associate with SRF but is defective in transcriptional activation, blocks cardiomyocyte hypertrophy induced by hypertrophic agonists such as phenylephrine and leukemia inhibitory factor. Myocardin-dependent hypertrophy can also be partially repressed by histone deacetylase 5, a transcriptional repressor of myocardin. These findings identify myocardin as a nuclear effector of hypertrophic signaling pathways that couples stress signals to a transcriptional program for postnatal cardiac growth and remodeling.
作为对压力信号的反应，出生后的心肌细胞经历肥大性生长，同时伴随着胎儿基因程序的激活、肌节的组装和细胞增大。我们发现，肥大信号刺激心肌转录辅激活因子的表达和转录活性，心肌转录辅激活因子是血清反应因子（SRF）在心脏和平滑肌中的特异性辅激活因子。与心肌转录辅激活因子作为肥大信号转导因子的作用一致，在心肌细胞中强制表达心肌转录辅激活因子足以替代肥大信号并诱导心肌细胞肥大和胎儿心脏基因程序。相反，一种显性负性突变形式的心肌转录辅激活因子，它保留了与SRF结合的能力，但在转录激活方面存在缺陷，可阻断由苯肾上腺素和白血病抑制因子等肥大激动剂诱导的心肌细胞肥大。依赖心肌转录辅激活因子的肥大也可被组蛋白脱乙酰基酶5部分抑制，组蛋白脱乙酰基酶5是心肌转录辅激活因子的一种转录抑制因子。这些发现确定心肌转录辅激活因子是肥大信号通路的核效应器，它将压力信号与出生后心脏生长和重塑的转录程序联系起来。
