Abstract 17913: The Long Non-coding Rna Malat1 Regulates Atherosclerosis in vivo
Long non-coding RNAs (lncRNAs) have been described to play a role in many biological processes, including epigenetic regulation of gene expression. We previously showed that the lncRNA MALAT1 regulates angiogenesis. Since MALAT1 is induced by atheroprotective laminar shear stress, we determined whether MALAT1 regulates atherosclerosis.
To address this question, we generated MALAT -/- ApoE -/- mice that were fed with a high fat diet for 12 weeks. Genetic deletion of MALAT1 in ApoE-/- mice increased plaque size as defined by oil red positive area in the aortic arch (+28.4+12%; n=5, p<0.05). However, pharmacological inhibition of MALAT1 by GapmeRs, which were directed against MALAT1 and injected every second week for 12 weeks, did not significantly affect plaque load or plaque size. To explain the discrepant results, we analyzed the expression of MALAT1, which was fully deleted in all analyzed cell types and tissues obtained from MALAT1-/- mice, whereas GapmeR-MALAT1 treatment efficiently silenced MALAT1 expression in all organs except circulating and splenic monocytes. These data suggest that inhibition of MALAT1 in inflammatory cells, which is not sufficiently accomplished by MALAT1 GapmeRs, may be necessary to modulate atherosclerotic disease progression. In line with this, infiltration of CD45+ cells was significantly augmented in MALAT1-/-ApoE-/- mice (+35.5+8.6%, n = 10, p<0.05) but not in GapmeR-treated ApoE-/- mice (-5.6+12.3%, n=10, ns).
Moreover, MALAT1 deletion significantly increased macrophages (+60.4+22.8%, n=10, p<0.05) and dendritic cells in the spleen (+37.4+17.5%, n=10) and augmented circulating monocytes (+70.2+70.2%, n=5, ns).
In conclusion, we show that genetic deletion but not pharmacological inhibition of MALAT1 enhances atherosclerotic lesion formation and augments splenic monocytes and hematopoietic cell recruitment to atherosclerotic plaques.
The causal involvement of MALAT1 expression in hematopoietic cells in atherogenesis is currently elucidated by bone marrow transplantation experiments.
Author Disclosures: K.M. Michalik: None. S. Cremer: None. A. Fischer: None. M. Muhly-Reinholz: None. L. Pfisterer: None. W. Poller: None. R. Boon: None. A.M. Zeiher: None. S. Dimmeler: Consultant/Advisory Board; Modest; Miragen. Research Grant; Significant; ERC, DFG.
- © 2015 by American Heart Association, Inc.