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. 2014 Dec 1;35(45):3224-31.
doi: 10.1093/eurheartj/ehu344. Epub 2014 Sep 12.

Vascular importance of the miR-212/132 cluster

Regalla Kumarswamy  1 , Ingo Volkmann  2 , Julia Beermann  2 , Lars Christian Napp  3 , Olga Jabs  3 , Raj Bhayadia  4 , Anette Melk  4 , Ahmet Ucar  5 , Kamal Chowdhury  6 , Johan M Lorenzen  7 , Shashi Kumar Gupta  2 , Sandor Batkai  7 , Thomas Thum  8
Affiliations

Vascular importance of the miR-212/132 cluster

Regalla Kumarswamy et al. Eur Heart J. .

Abstract

Rationale: Many processes in endothelial cells including angiogenic responses are regulated by microRNAs. However, there is limited information available about their complex cross-talk in regulating certain endothelial functions.

Aim: The objective of this study is to identify endothelial functions of the pro-hypertrophic miR-212/132 cluster and its cross-talk with other microRNAs during development and disease.

Methods and results: We here show that anti-angiogenic stimulation by transforming growth factor-beta activates the microRNA-212/132 cluster by derepression of their transcriptional co-activator cAMP response element-binding protein (CREB)-binding protein (CBP) which is a novel target of a previously identified pro-angiogenic miRNA miR-30a-3p in endothelial cells. Surprisingly, despite having the same seed-sequence, miR-212 and miR-132 exerted differential effects on endothelial transcriptome regulation and cellular functions with stronger endothelial inhibitory effects caused by miR-212. These differences could be attributed to additional auxiliary binding of miR-212 to its targets. In vivo, deletion of the miR-212/132 cluster increased endothelial vasodilatory function, improved angiogenic responses during postnatal development and in adult mice.

Conclusion: Our results identify (i) a novel miRNA-cross-talk involving miR-30a-3p and miR-212, which led to suppression of important endothelial genes such as GAB1 and SIRT1 finally culminating in impaired endothelial function; and (ii) microRNAs may have different biological roles despite having the same seed sequence.

Keywords: Angiogenesis; Endothelial cells; MicroRNAs; Sirtuins; Vascular function.

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