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Protective role of an lncRNA against atherosclerosis

January 2019. The molecule MALAT1, a long non-coding RNA, protects against atherosclerosis and plaque inflammation

In recent years, it became evident that the majority of the human genome is transcribed but only 2-3 % of the transcripts encode for proteins. A part of the non-coding genome is transcribed as "long non-coding RNAs" (lncRNAs). These RNAs can interfere with gene expression and post-transcriptional signaling at various levels. Some recent studies have suggested that lncRNAs play a crucial role in vascular biology and cardiovascular disease. The mechanisms underlying these reported functional effects of lncRNAs in the vasculature and their role in atherosclerosis are however largely unknown. Atherosclerosis is the major cause of vessel occlusion leading to myocardial infarction or stroke.

A team of scientists, led by Stefanie Dimmeler from Goethe University Frankfurt and the DZHK Partner Site Rhine-Main, investigated the effect of the lncRNA MALAT1 on atherosclerosis. MALAT1 is highly expressed in vascular and inflammatory cells and regulates endothelial and smooth muscle cell functions in vitro. Building on these results the scientists studied the role of this lncRNA in atherosclerotic lesion development in vivo.

Their results demonstrate for the first time the importance of a long non-coding RNA in atherosclerotic lesion development in mice and humans. The team showed that MALAT1 protects against atherosclerosis by regulating inflammation. MALAT1 deficiency in leukocytes led to increased myeloid cell adhesion to the vessel wall and increased cytokine production. The anti-inflammatory properties of MALAT1 were found to be at least in part mediated via interfering with microRNAs. The scientists detected reduced MALAT1 levels in atherosclerotic lesions of patients and reduced MALAT1 levels in human atherosclerotic lesions were associated with a poor prognosis.

Atherosclerosis might elicit dynamic changes in expression patterns of non-coding RNAs which could be exploited in the future, finally paving the way for therapeutics directed at RNAs.

Stefanie Dimmeler, Institute for Cardiovascular Regeneration, Centre of Molecular Medicine and DZHK Partner Site Rhine-Main , Goethe University and DZHK Partner Site Rhine-Main Frankfurt/Main, Germany, e-mail Dimmeler@em.uni-frankfurt.de

Cremer S, Michalik KM, Fischer A, Pfisterer L, Jaé N, Winter C, Boon RA, Muhly-Reinholz M, John D, Uchida S, Weber C, Poller W, Günther S, Braun T, Li DY, Maegdefessel L, Matic Perisic L, Hedin U, Soehnlein O, Zeiher A, Dimmeler S (2018) Hematopoietic deficiency of the long non-coding RNA MALAT1 promotes atherosclerosis and plaque inflammation. Circulation: first published online 28 November 2018. http://dx.doi.org/10.1161/circulationaha.117.029015