Expression Of The Long Non-Coding Rna Malat1 In Inflammatory Cells Controls Atherosclerosis And Plaque Inflammation In Mice And Humans

The majority of transcribed RNAs function as regulatory RNAs. We previously showed that lncRNA MALAT1 regulates angiogenesis. Since MALAT1 is induced by atheroprotective laminar flow, we hypothesized that it influences atherosclerosis. Therefore, we generated MALAT1 -/- ApoE -/- mice. These mice showed increased plaque size in the aortic arch (+28.4±12%; n=5, p -/- mice. CD45+ cells were significantly increased in plaques of MALAT1 -/- ApoE -/- mice (+35.5±8.6%, n=10, p -/- mice, but was not affected in circulating and splenic monocytes after GapmeR treatment. Therefore, we transplanted MALAT -/- and MALAT1 +/+ bone marrow cells in lethally irradiated MALAT +/+ ApoE -/- mice. Indeed, genetic deletion of MALAT1 in hematopoietic cells leads to increased plaque size (+62,3±9,18%, n=7, p Mechanistically, we demonstrate that lack of MALAT1 in leukocytes results in increased adhesion to endothelial cells. Since MALAT1 is predominantly expressed in neutrophils, we analyzed genes important for neutrophil function in MALAT1 -/- hematopoietic cells. We detected elevated levels of myeloperoxidase and elastase. Moreover, neutrophils derived from MALAT1 -/- mice secrete significantly higher amounts of proinflammatory cytokines (TNFα, CCL4, CXCL2) after stimulation with LPS. In line with this, MALAT1 levels in human plaques correlate inversely with TNFα and CXCL2. In conclusion, we show that genetic deletion of MALAT1 specifically in immune cells enhances atherosclerotic lesion formation and plaque inflammation in mice. Importantly, MALAT1 expression is reduced in human atherosclerotic lesions and associated with patient instability and increased mortality.