Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/- mice

Martina Gast, Bernhard H. Rauch, Shinichi Nakagawa, Arash Haghikia, Andrzej Jasina, Jan Haas, Neetika Nath, Lars Jensen, Andrea Stroux, Andreas Böhm, Julian Friebel, Ursula Rauch, Carsten Skurk, Stefan Blankenberg, Tanja Zeller, Prasanth Kumar Kannanganattu, Benjamin Meder, Andreas Kuss, Ulf Landmesser, Wolfgang Poller

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)302-314
Number of pages13
JournalCardiovascular research
Volume115
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Long Noncoding RNA
Apolipoproteins E
Immune System
Atherosclerosis
Neoplasm Metastasis
Tumor Necrosis Factor-alpha
Interferons
RNA Sequence Analysis
Adenocarcinoma of lung
MicroRNAs
Innate Immunity
Interleukin-6
Macrophages
CXC Chemokines
Granzymes
CC Chemokines
Myocarditis

Keywords

  • Atherosclerosis
  • Cardiovascular genetics
  • Immunoregulatory genes
  • Innate immunity
  • Long non-coding RNA

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Gast, M., Rauch, B. H., Nakagawa, S., Haghikia, A., Jasina, A., Haas, J., ... Poller, W. (2019). Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/- mice. Cardiovascular research, 115(2), 302-314. https://doi.org/10.1093/cvr/cvy202

Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/- mice. / 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; Kannanganattu, Prasanth Kumar; Meder, Benjamin; Kuss, Andreas; Landmesser, Ulf; Poller, Wolfgang.

In: Cardiovascular research, Vol. 115, No. 2, 01.02.2019, p. 302-314.

Research output: Contribution to journalArticle

Gast, M, Rauch, BH, Nakagawa, S, Haghikia, A, Jasina, A, Haas, J, Nath, N, Jensen, L, Stroux, A, Böhm, A, Friebel, J, Rauch, U, Skurk, C, Blankenberg, S, Zeller, T, Kannanganattu, PK, Meder, B, Kuss, A, Landmesser, U & Poller, W 2019, 'Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/- mice', Cardiovascular research, vol. 115, no. 2, pp. 302-314. https://doi.org/10.1093/cvr/cvy202
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 ; Kannanganattu, Prasanth Kumar ; Meder, Benjamin ; Kuss, Andreas ; Landmesser, Ulf ; Poller, Wolfgang. / Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/- mice. In: Cardiovascular research. 2019 ; Vol. 115, No. 2. pp. 302-314.
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title = "Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/- mice",
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.",
keywords = "Atherosclerosis, Cardiovascular genetics, Immunoregulatory genes, Innate immunity, Long non-coding RNA",
author = "Martina Gast and Rauch, {Bernhard H.} and Shinichi Nakagawa and Arash Haghikia and Andrzej Jasina and Jan Haas and Neetika Nath and Lars Jensen and Andrea Stroux and Andreas B{\"o}hm and Julian Friebel and Ursula Rauch and Carsten Skurk and Stefan Blankenberg and Tanja Zeller and Kannanganattu, {Prasanth Kumar} and Benjamin Meder and Andreas Kuss and Ulf Landmesser and Wolfgang Poller",
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TY - JOUR

T1 - Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/- mice

AU - Gast, Martina

AU - Rauch, Bernhard H.

AU - Nakagawa, Shinichi

AU - Haghikia, Arash

AU - Jasina, Andrzej

AU - Haas, Jan

AU - Nath, Neetika

AU - Jensen, Lars

AU - Stroux, Andrea

AU - Böhm, Andreas

AU - Friebel, Julian

AU - Rauch, Ursula

AU - Skurk, Carsten

AU - Blankenberg, Stefan

AU - Zeller, Tanja

AU - Kannanganattu, Prasanth Kumar

AU - Meder, Benjamin

AU - Kuss, Andreas

AU - Landmesser, Ulf

AU - Poller, Wolfgang

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Cardiovascular genetics

KW - Immunoregulatory genes

KW - Innate immunity

KW - Long non-coding RNA

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