Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE−/−mice. Issue 2 (8th August 2018)

• Record Type: Journal Article
• Authors: Gast, Martina; Rauch, Bernhard H; Nakagawa, Shinichi; Haghikia, Arash; Jasina, Andrzej; Haas, Jan; Nath, Neetika; Jensen, Lars; Stroux, Andrea; Böhm, Andreas; Friebel, Julian; Rauch, Ursula; Skurk, Carsten; Blankenberg, Stefan; Zeller, Tanja; Prasanth, Kannanganattu V; Meder, Benjamin; Kuss, Andreas; Landmesser, Ulf; Poller, Wolfgang
• Is Part Of: Cardiovascular research. Volume 115:Issue 2(2019)
• Page Start: 302
• Page End: 314
• Publication Date: 2018-08-08
• Subjects: Cardiovascular genetics -- Immunoregulatory genes -- Long non-coding RNA -- Innate immunity -- Atherosclerosis; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvy202
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: The immune system is considered a key driver of atherosclerosis, and beyond proteins and microRNAs (miRs), long non-coding RNAs (lncRNAs) are implicated in immune control. We previously described that lncRNA metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ) is involved in cardiac innate immunity in a myocarditis model. Here, we investigated the impact of MALAT1 deficiency upon atherosclerosis development. Methods and results: Heterozygous MALAT1 -deficient ApoE −/− mice displayed massive immune system dysregulation and atherosclerosis within 2 months even when kept on normal diet. Aortic plaque area ( P < 0.05) and aortic root plaque size ( P < 0.001) were increased in MALAT1 -deficient vs. MALAT1 -wildtype ApoE −/− mice. Serum levels of interferon-γ (IFN-γ), tumour necrosis factor (TNF), and interleukin 6 (IL6) were elevated ( P < 0.001) in MALAT1 -deficient animals. MALAT1 -deficient bone marrow-derived macrophages showed enhanced expression of TNF ( P = 0.001) and inducible NO synthase (NOS2) ( P = 0.002), suppressed MMP9 ( P < 0.001), and impaired phagocytic activity ( P < 0.001) upon lipopolysaccharide stimulation. RNA-sequencing revealed grossly altered transcriptomes of MALAT1 -deficient splenocytes already at baseline, with massive induction of IFN- γ, TNF, NOS2, and granzyme B; CC and CXC chemokines and CCR8; and innate immunity genes interferon-induced protein with tetratricopeptide repeats (IFIT)1/3, interferon-induced transmembrane protein (IFITM)1/3, ISG15. Multiple miRs were up to 45-fold upregulated. Further, selective ablation of the cytosolic part of the MALAT1 system only, the enzymatically MALAT1 -derived mascRNA, resulted in massive induction of TNF ( P = 0.004) and IL6 ( P = 0.028) in macrophages. Northern analysis of post-myocardial infarction patient vs. control peripheral blood mononuclear cells showed reduced ( P = 0.005) mascRNA in the patients. CHART -enriched RNA-sequencing reads at the genomic loci of MALAT1 and neighbouring nuclear enriched abundant transcript ( NEAT1 ) documented direct interaction between these lncRNA transcripts. Conclusion: The data suggest a molecular circuit involving the MALAT1 -mascRNA system, interactions between MALAT1 and NEAT1, and key immune effector molecules, cumulatively impacting upon the development of atherosclerosis. It appears reasonable to look for therapeutic targets in this circuit and to screen for anomalies in the NEAT1–MALAT1 region in humans, too, as possible novel disease risk factors.