Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster
Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster
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DOI：
10.1172/jci38864
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发表时间：
2009-09-01
影响因子：
15.9
通讯作者：
Braun, Thomas
中科院分区：
文献类型：
--
作者：
Boettger, Thomas;Beetz, Nadine;Braun, Thomas
VSMC通过将其表型从收缩型调整为合成型来响应局部环境的变化，这种现象称为表型调节或转换。血管平滑肌细胞不能获得和维持收缩表型在许多主要的人类疾病中起关键作用，包括动脉硬化。虽然已经确定了几种控制SMC分化的调节回路，但支配表型调节的决定性机制仍然未知。在这里，我们证明了小鼠miR-143/145簇，其表达仅限于SMC在发展过程中，是所需的VSMC收购的收缩表型。来自miR-143/145缺陷小鼠的VSMC被锁定在合成状态，这使其收缩能力丧失并有利于新生内膜病变的发展。使用稳定同位素标记的参考小鼠进行无偏高通量、定量、基于质谱的蛋白质组学，可以识别miR-143/145靶点;这些靶点包括血管紧张素转换酶（ACE），其可能影响VSMC的合成表型和收缩功能。ACE或AT受体的药理学抑制部分逆转了miR-143/145缺陷小鼠的血管功能障碍并使基因表达正常化。我们的结论是，操纵miR-143/145的表达可能会提供一个新的方法来影响血管修复和衰减动脉粥样硬化的发病机制。
VSMCs respond to changes in the local environment by adjusting their phenotype from contractile to synthetic, a phenomenon known as phenotypic modulation or switching. Failure of VSMCs to acquire and maintain the contractile phenotype plays a key role in a number of major human diseases, including arteriosclerosis. Although several regulatory circuits that control differentiation of SMCs have been identified, the decisive mechanisms that govern phenotypic modulation remain unknown. Here, we demonstrate that the mouse miR-143/145 cluster, expression of which is confined to SMCs during development, is required for VSMC acquisition of the contractile phenotype. VSMCs from miR-143/145-deficient mice were locked in the synthetic state, which incapacitated their contractile abilities and favored neointimal lesion development. Unbiased high-throughput, quantitative, mass spectrometry-based proteomics using reference mice labeled with stable isotopes allowed identification of miR-143/145 targets; these included angiotensin-converting enzyme (ACE), which might affect both the synthetic phenotype and contractile functions of VSMCs. Pharmacological inhibition of either ACE or the AT, receptor partially reversed vascular dysfunction and normalized gene expression in miR-143/145-deficient mice. We conclude that manipulation of miR-143/145 expression may offer a new approach for influencing vascular repair and attenuating arteriosclerotic pathogenesis.