MicroRNA-26a is a novel regulator of vascular smooth muscle cell function.
MicroRNA-26a is a novel regulator of vascular smooth muscle cell function.
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DOI：
10.1002/jcp.22422
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发表时间：
2011-04
影响因子：
5.6
通讯作者：
Spin, Joshua M.
中科院分区：
文献类型：
--
作者：
Leeper, Nicholas J.;Raiesdana, Azad;Kojima, Yoko;Chun, Hyung J.;Azuma, Junya;Maegdefessel, Lars;Kundu, Ramendra K.;Quertermous, Thomas;Tsao, Philip S.;Spin, Joshua M.
异常平滑肌细胞（SMC）可塑性与多种血管疾病有关，包括动脉粥样硬化、再狭窄和腹主动脉瘤（AAA）形成。虽然控制这一过程的途径尚不清楚，但已在SMC中证实了特定microRNA（miRNAs）的表观遗传调控。我们假设额外的miRNAs可能在决定血管SMC表型中起重要作用。对人主动脉SMC进行miRNA的微阵列分析，其经历响应于血清戒断的表型转换，并鉴定了31个显著调节的实体。我们选择高度保守的候选miRNA-26 a进行进一步的研究。抑制miRNA-26 a可加速SMC分化，促进细胞凋亡，同时抑制增殖和迁移。miRNA-26 a的过表达减弱了分化。作为一种潜在的机制，我们研究了miRNA-26 a是否影响TGF-β通路信号传导。双荧光素酶报告基因分析表明，在转染的人细胞中，miRNA-26 a抑制增强了SMAD信号传导，而miRNA-26 a过表达则产生了相反的效果。此外，抑制miRNA-26 a增加SMAD-1和SMAD-4的基因表达，而过表达抑制SMAD-1。microRNA-26 a在两种AAA形成的小鼠模型中也被发现下调（2.5至3.8倍降低，P < 0.02），其中发生从收缩表型到合成表型的增强转换。总之，miRNA-26 a促进血管SMC增殖，同时抑制细胞分化和凋亡，并改变TGF-β通路信号传导。microRNA-26 a代表SMC生物学的重要新调节因子和AAA疾病的潜在治疗靶点。
Aberrant smooth muscle cell (SMC) plasticity has been implicated in a variety of vascular disorders including atherosclerosis, restenosis, and abdominal aortic aneurysm (AAA) formation. While the pathways governing this process remain unclear, epigenetic regulation by specific microRNAs (miRNAs) has been demonstrated in SMCs. We hypothesized that additional miRNAs might play an important role in determining vascular SMC phenotype. Microarray analysis of miRNAs was performed on human aortic SMCs undergoing phenotypic switching in response to serum withdrawal, and identified 31 significantly regulated entities. We chose the highly conserved candidate miRNA-26a for additional studies. Inhibition of miRNA-26a accelerated SMC differentiation, and also promoted apoptosis, while inhibiting proliferation and migration. Overexpression of miRNA-26a blunted differentiation. As a potential mechanism, we investigated whether miRNA-26a influences TGF-β-pathway signaling. Dual-luciferase reporter assays demonstrated enhanced SMAD signaling with miRNA-26a inhibition, and the opposite effect with miRNA-26a overexpression in transfected human cells. Furthermore, inhibition of miRNA-26a increased gene expression of SMAD-1 and SMAD-4, while overexpression inhibited SMAD-1. MicroRNA-26a was also found to be downregulated in two mouse models of AAA formation (2.5- to 3.8-fold decrease, P < 0.02) in which enhanced switching from contractile to synthetic phenotype occurs. In summary, miRNA-26a promotes vascular SMC proliferation while inhibiting cellular differentiation and apoptosis, and alters TGF-β pathway signaling. MicroRNA-26a represents an important new regulator of SMC biology and a potential therapeutic target in AAA disease.
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