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MicroRNA-mediated mechanisms of the cellular stress response in atherosclerosis

Nature Reviews Cardiology volume 12, pages 361–374 (2015)Cite this article

Subjects

An Erratum to this article was published on 03 December 2015

This article has been updated

Key Points

  • Atherosclerosis develops mainly at branching points of large-sized and medium-sized arteries, where flow turbulence triggers chronic endothelial injury

  • MicroRNAs (miRNAs) regulate endothelial regeneration at athero-susceptible sites by linking proliferative and inflammatory responses

  • The endothelial proliferative reserve is controlled by flow-regulated miRNAs and determines endothelial regeneration processes in response to additional injuries (such as hyperlipidaemia or oxidative stress)

  • miRNA expression in macrophages drives the switch from anti-inflammatory to proinflammatory phenotypes and contributes to chronic inflammation in atherosclerotic plaques

  • Inhibition or overexpression of specific miRNAs is a promising treatment strategy for atherosclerosis

Abstract

Atherosclerosis is characterised by the accumulation of lipid-laden macrophages in atherosclerotic lesions and occurs preferentially at arterial branching points, which are prone to inflammation during hyperlipidaemic stress. The increased susceptibility at branching sites of arteries is attributable to poor adaptation of arterial endothelial cells to disturbed blood flow. In the past 5 years, several studies have provided mechanistic insights into the regulatory roles of microRNAs (miRNAs) in inflammatory activation, proliferation, and regeneration of endothelial cells during this maladaptive process. The intercellular transfer of vesicle-bound miRNAs contributes to arterial homeostasis, and the combinatorial effect of multiple miRNAs controls the unresolved inflammation orchestrated by macrophages in atherosclerotic lesions. In this Review, we highlight the miRNA-dependent regulation of the endothelial phenotype and the proliferative reserve that occurs in response to altered haemodynamic conditions as a prerequisite for atherogenic inflammation. In particular, we discuss the regulation of transcriptional modules by miRNAs and the protective role of complementary strand pairs, which encompasses remote miRNA signalling. In addition, we review the roles of miRNA tandems and describe the relevance of RNA target selection and competition to the behaviour of lesional macrophages. Elucidating miRNA-mediated regulatory mechanisms can aid the development of novel diagnostic and therapeutic strategies for atherosclerosis.

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Figure 1: Important signalling pathways in the maladaptive response of endothelial cells to disturbed flow.
Figure 2: The two-hit model of endothelial damage and repair in atherosclerosis.
Figure 3: miRNA interactome in endothelial cells exposed to disturbed flow.
Figure 4: miRNAs control the inflammatory response and cholesterol metabolism in macrophages.

Change history

  • 03 December 2015

    In the version of this article initially published online and in print, the mechanisms by which microRNA 146a modulates post-transcriptional proinflammatory pathways were incorrectly described on page 368. The error has been corrected for the print, HTML, and PDF versions of the article.

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Acknowledgements

A.S. and C.W. acknowledge support from the Deutsche Forschungsgemeinschaft (SFB 1123-B4), the German Centre for Cardiovascular Research (MHA VD 1.2), and the German Federal Ministry of Education and Research (grant number 01KU1213A).

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  1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Pettenkoferstrasse 9, 80336, Munich, Germany

    Andreas Schober, Maliheh Nazari-Jahantigh & Christian Weber

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M.N.-J. researched data for the article. All the authors wrote, reviewed, and edited the article before submission.

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Schober, A., Nazari-Jahantigh, M. & Weber, C. MicroRNA-mediated mechanisms of the cellular stress response in atherosclerosis. Nat Rev Cardiol 12, 361–374 (2015). https://doi.org/10.1038/nrcardio.2015.38

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