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22431733
Small RNA sequencing reveals microRNAs that modulate angiotensin II effects in vascular smooth muscle cells.

J Biol Chem, 2012/5/04;287(19):15672-83.

Jin W[1], Reddy MA, Chen Z, Putta S, Lanting L, Kato M, Park JT, Chandra M, Wang C, Tangirala RK, Natarajan R

Affiliations

PMID: 22431733DOI: 10.1074/jbc.M111.322669

Impact factor: 5.486

Abstract
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 up-regulation 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.
MeSH terms
3' Untranslated Regions; Angiotensin II; Animals; Blotting, Western; Cells, Cultured; Chemokine CCL2; Cyclic AMP Response Element-Binding Protein; DNA, Complementary; Gene Expression; Gene Expression Profiling; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; PTEN Phosphohydrolase; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA
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