Small RNA Sequencing Reveals MicroRNAs That Modulate Angiotensin II Effects in Vascular Smooth Muscle Cells

被引：75

作者：

Jin, Wen ^{[1
,2
]}

Reddy, Marpadga A. ^{[1
]}

Chen, Zhuo ^{[1
]}

Putta, Sumanth ^{[1
]}

Lanting, Linda ^{[1
]}

Kato, Mitsuo ^{[1
]}

Park, Jung Tak ^{[1
]}

Chandra, Manasa ^{[2
]}

Wang, Charles ^{[3
]}

Tangirala, Rajendra K. ^{[4
]}

Natarajan, Rama ^{[1
,2
]}

机构：

[1] City Hope Natl Med Ctr, Dept Diabet, Beckman Res Inst, Div Mol Diabet Res, Duarte, CA 91010 USA

[2] City Hope Natl Med Ctr, Irell & Manella Grad Sch Biol Sci, Beckman Res Inst, Duarte, CA 91010 USA

[3] City Hope Natl Med Ctr, Funct Genom Core, Beckman Res Inst, Dept Mol Med, Duarte, CA 91010 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2012年 / 287卷 / 19期

基金：

美国国家卫生研究院;

关键词：

ELEMENT-BINDING PROTEIN; MONOCYTE CHEMOATTRACTANT PROTEIN-1; FACTOR-KAPPA-B; NEOINTIMAL LESION FORMATION; TUMOR-SUPPRESSOR PROTEIN; ACCELERATED ATHEROSCLEROSIS; GENE-EXPRESSION; DEFICIENT MICE; PTEN; INHIBITION;

D O I：

10.1074/jbc.M111.322669

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 (VSMC) 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 dose-dependent 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 at least in part via PTEN repression in rat VSMC. Moreover, miR-132 overexpression enhanced cyclic AMP-response element-binding protein (CREB) phosphorylation via RASA1 (p120 Ras GTPase-activating protein 1) down-regulation, whereas miR-132 inhibition attenuated Ang II-induced CREB activation. Furthermore, miR-132 up-regulation by Ang II required CREB activation, demonstrating a positive feedback loop. Notably, aortas from Ang II-infused mice displayed similar up-regulation of miR-132/212 and monocyte chemoattractant protein-1, supporting in vivo relevance. In addition, microarray analysis and reverse transcriptase-quantitative PCR validation revealed additional novel miR-132 targets among Ang II-down-regulated 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.

引用

页码：15672 / 15683

页数：12

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