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

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.

The role of lncRNA MALAT1 in cardiovascular disease

“…In addition, MALAT1 was also up‐regulated in ox‐LDL treated macrophages, accompanied by increase of CD36 expression by recruiting β‐catenin to binding sites on the CD36 promoter . CD36 induced by MALAT1 could facilitate lipid uptake and promote subsequent atherosclerotic plaque formation …”

“…Knockdown of MALAT1 caused increased plaque size and infiltration of inflammatory CD45 + cells partly via regulation of miR‐503 . Furthermore, MALAT1 were also involved in regulation of endothelial dysfunction, lipid accumulation and chronic inflammation, which contributed to development of atherosclerosis …”

“…41 Furthermore, MALAT1 were also involved in regulation of endothelial dysfunction, lipid accumulation and chronic inflammation, which contributed to development of atherosclerosis. 40,42,43…”

“…50 CD36 induced by MALAT1 could facilitate lipid uptake and promote subsequent atherosclerotic plaque formation. 42…”

Long non‐coding RNA SNHG16 regulates human aortic smooth muscle cell proliferation and migration via sponging miR‐205 and modulating Smad2

“…Recently, it has also been reported that lncRNAs involve in the pathogenesis of CVDs. For example, the lncRNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) was decreased in human plaques and down‐regulation of MALAT1 was correlated with poor prognosis of CVDs . LincRNA‐p21 was reported to regulate VSMC proliferation and atherosclerotic formation via the enhancement of p53 activity .…”