在心血管疾病中，AngII對平滑肌細胞的功能失調(diào)起著決定性作用,。但是,，miRNA在這個過程中的作用還不明確。最近,，美國貝克曼研究所Rama Natarajan等人研究發(fā)現(xiàn)：作為一種新發(fā)現(xiàn)的AngII調(diào)節(jié)分子miR-132/212,，AngII可以通過上調(diào)血管平滑肌細胞中的miR-132水平，引起MCP-1局部作用于PTEN,，并激活CREB,，以此來調(diào)節(jié)與細胞周期和細胞運動有關(guān)的基因。相關(guān)論文發(fā)表在3月19日的美國《生化周刊》（Journal of Biological Chemistry）上,。
在這項研究中,，研究人員使用了小RNA深度測序來評測小鼠平滑肌細胞(RVSMC)中由AngII調(diào)節(jié)的miRNA，并評估它們在VSMC功能失調(diào)中所起的作用,。從測序結(jié)果中,，研究人員發(fā)現(xiàn)了幾種應答AngII的miRNA，由生物信息學分析表明,，這些miRNA可以調(diào)節(jié)與心血管疾病有關(guān)的生物過程,。對高度誘導的miR-132和 miR-212簇（miR-132/212)的進一步研究表明：AngII通過作用于AngII 1型受體,，miR-132/212表現(xiàn)出時間以及劑量依賴性上調(diào)。
研究者通過鑒定發(fā)現(xiàn),，同源性磷酸酶張力蛋白(PTEN)是miR-132的一個新發(fā)現(xiàn)的靶點,。他們證明，在RVSMC中miR-132之所以可以誘導單核細胞趨化蛋白1(MCP-1),，至少部分是由于PTEN被抑制,。此外，miR-132的過表達會通過下調(diào)RASA1來增強cAMP反應元件結(jié)合蛋白（CREB）的磷酸化,，但是抑制miR-132減弱了AngII引起的CREB的激活作用,。
再者，通過AngII引起的miR-132上調(diào)需要CREB的激活,。對應于上面的反應,，這正是一個正反饋環(huán)路。在實驗中,，服用過AngII的小鼠的主動脈表現(xiàn)出相似的miR-132/212及MCP-1的上調(diào),。除此之外，顯微陣列分析和RT-QPCR驗證了在AngII下調(diào)與細胞周期,、細胞運動以及心血管功能有關(guān)基因中的另外一個miR-132新靶標,。
這些結(jié)果表明，miR132/212能夠作為一個新型的細胞分子來調(diào)整和擴大AngII在VSMC中的作用,。因此,，它很有可能成為由AngII引起的心血管疾病新的藥物靶點。（生物谷Deepblue編譯）
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.
