在心血管疾病中，AngII对平滑肌细胞的功能失调起着决定性作用。但是，miRNA在这个过程中的作用还不明确。最近，美国贝克曼研究所Rama Natarajan等人研究发现：作为一种新发现的AngII调节分子miR-132/212，AngII可以通过上调血管平滑肌细胞中的miR-132水平，引起MCP-1局部作用于PTEN，并激活CREB，以此来调节与细胞周期和细胞运动有关的基因。相关论文发表在3月19日的美国《生化周刊》（Journal of Biological Chemistry）上。
在这项研究中，研究人员使用了小RNA深度测序来评测小鼠平滑肌细胞(RVSMC)中由AngII调节的miRNA，并评估它们在VSMC功能失调中所起的作用。从测序结果中，研究人员发现了几种应答AngII的miRNA，由生物信息学分析表明，这些miRNA可以调节与心血管疾病有关的生物过程。对高度诱导的miR-132和 miR-212簇（miR-132/212)的进一步研究表明：AngII通过作用于AngII 1型受体，miR-132/212表现出时间以及剂量依赖性上调。
研究者通过鉴定发现，同源性磷酸酶张力蛋白(PTEN)是miR-132的一个新发现的靶点。他们证明，在RVSMC中miR-132之所以可以诱导单核细胞趋化蛋白1(MCP-1)，至少部分是由于PTEN被抑制。此外，miR-132的过表达会通过下调RASA1来增强cAMP反应元件结合蛋白（CREB）的磷酸化，但是抑制miR-132减弱了AngII引起的CREB的激活作用。
再者，通过AngII引起的miR-132上调需要CREB的激活。对应于上面的反应，这正是一个正反馈环路。在实验中，服用过AngII的小鼠的主动脉表现出相似的miR-132/212及MCP-1的上调。除此之外，显微阵列分析和RT-QPCR验证了在AngII下调与细胞周期、细胞运动以及心血管功能有关基因中的另外一个miR-132新靶标。
这些结果表明，miR132/212能够作为一个新型的细胞分子来调整和扩大AngII在VSMC中的作用。因此，它很有可能成为由AngII引起的心血管疾病新的药物靶点。（生物谷Deepblue编译）
doi: 10.1074/jbc.M111.322669
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Small RNA sequencing reveals microRNAs that modulate angiotensin II effects in vascular smooth muscle cells
Wen Jin1, Marpadga A. Reddy, Zhuo Chen, Sumanth Putta, Linda Lanting, Mitsuo Kato, Jung Tak Park, Manasa Chandra, Charles Wang, Rajendra Tangirala and Rama Natarajan.
Angiotensin II (Ang II)-mediated vascular smooth muscle cell dysfunction plays a critical role in cardiovascular diseases. However, the role of microRNAs (miRNAs) in this process is unclear. We used small RNA deep sequencing to profile Ang II-regulated miRNAs in rat vascular smooth muscle cells (RVSMC) and evaluated their role in VSMC dysfunction.Sequencing results revealed several Ang II responsive miRNAs and bioinformatics analysis showed that their predicted targets can modulate biological processes relevant to cardiovascular diseases. Further studies with the most highly induced miR-132 and miR-212 cluster (miR-132/212) showed time- and dosedependent upregulation of miR-132/212 by Ang II through the Ang II Type 1 receptor. We identified phosphatase and tensin homolog (PTEN) as a novel target of miR-132 and demonstrated that miR-132 induces monocyte chemoattractant protein-1 (MCP-1) at least in part via PTEN repression in RVSMC. Moreover, miR-132 overexpression enhanced cyclic AMP-response element binding protein (CREB) phosphorylation via RASA1 downregulation, whereas miR-132 inhibition attenuated Ang II-induced CREB activation. Furthermore, miR-132 upregulation by Ang II required CREB activation, demonstrating a positive feedback loop. Notably, aortas from Ang II-infused mice displayed similar upregulation of miR-132/212 and MCP-1, supporting in vivo relevance. In addition, microarray analysis and RT-QPCR validation revealed additional novel miR-132 targets among Ang II downregulated genes implicated in cell cycle, motility and cardiovascular functions. These results suggest that miR132/212 can serve as a novel cellular node to fine-tune and amplify Ang II actions in VSMC.
