Hematopoietic Deficiency of the Long Noncoding RNA MALAT1 Promotes Atherosclerosis and Plaque Inflammation

Sebastian Cremer, Katharina M. Michalik, Ariane Fischer, Larissa Pfisterer, Nicolas Jae, Carla Winter, Reinier A. Boon, Marion Muhly-Reinholz, David John, Shizuka Uchida, Christian Weber, Wolfgang Poller, Stefan Guenther, Thomas Braun, Daniel Y. Li, Lars Maegdefessel, Ljubica Perisic Matic, Ulf Hedin, Oliver Soehnlein, Andreas ZeiherStefanie Dimmeler*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: The majority of the human genome comprises noncoding sequences, which are in part transcribed as long noncoding RNAs (lncRNAs). lncRNAs exhibit multiple functions, including the epigenetic control of gene expression. In this study, the effect of the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) on atherosclerosis was examined.

Methods: The effect of MALAT1 on atherosclerosis was determined in apolipoprotein E-deficient (Apoe(-/-)) MALAT1-deficient (Malat1(-/-)) mice that were fed with a high-fat diet and by studying the regulation of MALAT1 in human plaques.

Results: Apoe(-/-) Malat1(-/-) mice that were fed a high-fat diet showed increased plaque size and infiltration of inflammatory CD45(+) cells compared with Apoe(-/-) Malat1(+/+) control mice. Bone marrow transplantation of Apoe(-/-) Malat1(-/-) bone marrow cells in Apoe(-/-) Malat1(+/+) mice enhanced atherosclerotic lesion formation, which suggests that hematopoietic cells mediate the proatherosclerotic phenotype. Indeed, bone marrow cells isolated from Malat1(-/-) mice showed increased adhesion to endothelial cells and elevated levels of proinflammatory mediators. Moreover, myeloid cells of Malat1(-/-) mice displayed enhanced adhesion to atherosclerotic arteries in vivo. The anti-inflammatory effects of MALAT1 were attributed in part to reduction of the microRNA miR-503. MALAT1 expression was further significantly decreased in human plaques compared with normal arteries and was lower in symptomatic versus asymptomatic patients. Lower levels of MALAT1 in human plaques were associated with a worse prognosis.

Conclusions: Reduced levels of MALAT1 augment atherosclerotic lesion formation in mice and are associated with human atherosclerotic disease. The proatherosclerotic effects observed in Malat1(-/-) mice were mainly caused by enhanced accumulation of hematopoietic cells.

Original languageEnglish
Pages (from-to)1320-1334
Number of pages15
JournalCirculation
Volume139
Issue number10
DOIs
Publication statusPublished - 5 Mar 2019

Keywords

  • atherosclerosis
  • leukocytes
  • inflammation
  • RNA
  • COMPETING ENDOGENOUS RNA
  • LNCRNA MALAT1
  • EXPRESSION
  • CANCER
  • MIGRATION
  • INVASION
  • BINDING
  • CELLS
  • MIRNA

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