Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice
Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice
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DOI：
10.1172/jc133304
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发表时间：
2008-02-01
影响因子：
15.9
通讯作者：
Parmacek, Michael S.
中科院分区：
文献类型：
--
作者：
Huang, Jianhe;Cheng, Lan;Parmacek, Michael S.
Myocardin(MYOCD)是一种有效的转录辅助激活因子，与心血管发育和心血管系统对血流动力学应激的适应有关。为了确定Myocardin在心血管系统发育中的作用，建立了MYOCD(F/F)/Wnt1-Cre(+)和MYOCD(F/F)/Pax3-Cre(+)小鼠，选择性地将MYOCD(F/F)/Pax3-Cre(+)小鼠的MYOCD(F/F)/Wnt1-Cre(+)和MYOCD(F/F)/Pax3-Cre(+)小鼠的MYOCD(F/F)和MYOCD(F/F)/Pax3-Cre(MYOCD(F/F)/Wnt1-Cre(+)和MYOCD(F/F)/Pax3-Cre(+)突变小鼠均存活至出生，但在出生后3天前死于动脉导管未闭(PDA)。分布于动脉导管(DA)和大动脉的神经脊来源的SMC在编码SMC限制性收缩蛋白的肌钙蛋白调节基因的表达上表现出细胞自主阻断。此外，分布于DA的MYOCD缺乏的血管SMC表现出与SMC合成表型有关的超微结构特征，而不是收缩表型。与这些发现一致的是，从MYOCD条件性突变小鼠的原代主动脉SMC中去除MYOCD基因导致SMC收缩蛋白表达显著减少。综上所述，这些数据表明，myocardin调节神经沟来源的SMC收缩表型所需的基因的表达，并为可能支持PDA的分子和遗传程序提供新的见解。
Myocardin (Myocd) is a potent transcriptional coactivator that has been implicated in cardiovascular development and adaptation of the cardiovascular system to hemodynamic stress. To determine the function of myocardin in the developing cardiovascular system, Myocd(F/F)/Wnt1-Cre(+) and Myocd(F/F)/Pax3-Cre(+) mice were generated in which the myocardin gene was selectively ablated in neural crest-derived SMCs populating the cardiac outflow tract and great arteries. Both Myocd(F/F)/Wnt1-Cre(+) and Myocd(F/F)/Pax3-Cre(+) mutant mice survived to birth, but died prior to postnatal day 3 from patent ductus arteriosus (PDA). Neural crest-derived SMCs populating the ductus arteriosus (DA) and great arteries exhibited a cell autonomous block in expression of myocardin-regulated genes encoding SMC-restricted contractile proteins. Moreover, Myocd-deficient vascular SMCs populating the DA exhibited ultrastructural features generally associated with the SMC synthetic, rather than contractile, phenotype. Consistent with these findings, ablation of the Myocd gene in primary aortic SMCs harvested from Myocd conditional mutant mice caused a dramatic decrease in SMC contractile protein expression. Taken together, these data demonstrate that myocardin regulates expression of genes required for the contractile phenotype in neural crest-derived SMCs and provide new insights into the molecular and genetic programs that may underlie PDA.