Runx2 represses myocardin-mediated differentiation and facilitates osteogenic conversion of vascular smooth muscle cells
Runx2 represses myocardin-mediated differentiation and facilitates osteogenic conversion of vascular smooth muscle cells
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DOI：
10.1128/mcb.01771-07
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发表时间：
2008-02-01
影响因子：
5.3
通讯作者：
Kurabayashi, Masahiko
中科院分区：
文献类型：
--
作者：
Tanaka, Toru;Sato, Hiroko;Kurabayashi, Masahiko
表型可塑性和血管平滑肌细胞（SMC）的转换在动脉粥样硬化中起着关键作用。虽然Runx 2，一个关键的成骨转录因子，在动脉粥样硬化斑块中表达，但Runx 2调节SMC分化的分子机制仍不清楚。在这里，我们证明了Runx 2抑制平滑肌细胞分化诱导的心肌蛋白，作为血清反应因子（SRF）的共激活剂。与野生型小鼠相比，来自Runx 2基因缺失小鼠的小鼠胚胎成纤维细胞中，心肌梗塞素介导的SMC基因表达诱导增强。Runx 2的强制表达降低了SMC基因的表达，促进成骨基因的表达，而Runx 2的表达减少小干扰RNA增强SMC在人主动脉SMC的分化。Runx 2与SRF相互作用并干扰SRF/myocardin三元复合物的形成。因此，这项研究提供了第一个证据，Runx 2抑制SRF依赖的转录，作为一个辅阻遏独立于其DNA结合。我们认为Runx 2在成骨转化中起着关键作用，与动脉粥样硬化病变中SMC表型的抑制紧密相关。
Phenotypic plasticity and the switching of vascular smooth muscle cells (SMCs) play a critical role in atherosclerosis. Although Runx2, a key osteogenic transcription factor, is expressed in atherosclerotic plaques, the molecular mechanisms by which Runx2 regulates SMC differentiation remain unclear. Here we demonstrated that Runx2 repressed SMC differentiation induced by myocardin, which acts as a coactivator for serum response factor (SRF). Myocardin-mediated induction of SMC gene expression was enhanced in mouse embryonic fibroblasts derived from Runx2 null mice compared to wild-type mice. Forced expression of Runx2 decreased the expression of SMC genes and promoted osteogenic gene expression, whereas the reduction of Runx2 expression by small interfering RNA enhanced SMC differentiation in human aortic SMCs. Runx2 interacted with SRF and interfered with the formation of the SRF/myocardin ternary complex. Thus, this study provides the first evidence that Runx2 inhibits SRF-dependent transcription, as a corepressor independent of its DNA binding. We propose that Runx2 plays a pivotal role in osteogenic conversion tightly coupled with repression of the SMC phenotype in atherosclerotic lesions.