Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients
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Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients. / Gast, Martina; Rauch, Bernhard H; Haghikia, Arash; Nakagawa, Shinichi; Haas, Jan; Stroux, Andrea; Schmidt, David; Schumann, Paul; Weiss, Stefan; Jensen, Lars; Kratzer, Adelheid; Kraenkel, Nicolle; Müller, Christian; Börnigen, Daniela; Hirose, Tetsuro; Blankenberg, Stefan; Escher, Felicitas; Kühl, Anja A; Kuss, Andreas W; Meder, Benjamin; Landmesser, Ulf; Zeller, Tanja; Poller, Wolfgang.
In: CARDIOVASC RES, Vol. 115, No. 13, 01.11.2019, p. 1886-1906.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients
AU - Gast, Martina
AU - Rauch, Bernhard H
AU - Haghikia, Arash
AU - Nakagawa, Shinichi
AU - Haas, Jan
AU - Stroux, Andrea
AU - Schmidt, David
AU - Schumann, Paul
AU - Weiss, Stefan
AU - Jensen, Lars
AU - Kratzer, Adelheid
AU - Kraenkel, Nicolle
AU - Müller, Christian
AU - Börnigen, Daniela
AU - Hirose, Tetsuro
AU - Blankenberg, Stefan
AU - Escher, Felicitas
AU - Kühl, Anja A
AU - Kuss, Andreas W
AU - Meder, Benjamin
AU - Landmesser, Ulf
AU - Zeller, Tanja
AU - Poller, Wolfgang
N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - AIMS: Inflammation is a key driver of atherosclerosis and myocardial infarction (MI), and beyond proteins and microRNAs (miRs), long noncoding RNAs (lncRNAs) have been implicated in inflammation control. To obtain further information on the possible role of lncRNAs in the context of atherosclerosis, we obtained comprehensive transcriptome maps of circulating immune cells (peripheral blood mononuclear cells, PBMCs) of early onset MI patients. One lncRNA significantly suppressed in post-MI patients was further investigated in a murine knockout model.METHODS AND RESULTS: Individual RNA-sequencing (RNA-seq) was conducted on PBMCs from 28 post-MI patients with a history of MI at age ≤50 years and stable disease ≥3 months before study participation, and from 31 healthy individuals without manifest cardiovascular disease or family history of MI as controls. RNA-seq revealed deregulated protein-coding transcripts and lncRNAs in post-MI PBMCs, among which nuclear enriched abundant transcript (NEAT1) was the most highly expressed lncRNA, and the only one significantly suppressed in patients. Multivariate statistical analysis of validation cohorts of 106 post-MI patients and 85 controls indicated that the PBMC NEAT1 levels were influenced (P = 0.001) by post-MI status independent of statin intake, left ventricular ejection fraction, low-density lipoprotein or high-density lipoprotein cholesterol, or age. We investigated NEAT1-/- mice as a model of NEAT1 deficiency to evaluate if NEAT1 depletion may directly and causally alter immune regulation. RNA-seq of NEAT1-/- splenocytes identified disturbed expression and regulation of chemokines/receptors, innate immunity genes, tumour necrosis factor (TNF) and caspases, and increased production of reactive oxygen species (ROS) under baseline conditions. NEAT1-/- spleen displayed anomalous Treg and TH cell differentiation. NEAT1-/- bone marrow-derived macrophages (BMDMs) displayed altered transcriptomes with disturbed chemokine/chemokine receptor expression, increased baseline phagocytosis (P < 0.0001), and attenuated proliferation (P = 0.0013). NEAT1-/- BMDMs responded to LPS with increased (P < 0.0001) ROS production and disturbed phagocytic activity (P = 0.0318). Monocyte-macrophage differentiation was deregulated in NEAT1-/- bone marrow and blood. NEAT1-/- mice displayed aortic wall CD68+ cell infiltration, and there was evidence of myocardial inflammation which could lead to severe and potentially life-threatening structural damage in some of these animals.CONCLUSION: The study indicates distinctive alterations of lncRNA expression in post-MI patient PBMCs. Regarding the monocyte-enriched NEAT1 suppressed in post-MI patients, the data from NEAT1-/- mice identify NEAT1 as a novel lncRNA-type immunoregulator affecting monocyte-macrophage functions and T cell differentiation. NEAT1 is part of a molecular circuit also involving several chemokines and interleukins persistently deregulated post-MI. Individual profiling of this circuit may contribute to identify high-risk patients likely to benefit from immunomodulatory therapies. It also appears reasonable to look for new therapeutic targets within this circuit.
AB - AIMS: Inflammation is a key driver of atherosclerosis and myocardial infarction (MI), and beyond proteins and microRNAs (miRs), long noncoding RNAs (lncRNAs) have been implicated in inflammation control. To obtain further information on the possible role of lncRNAs in the context of atherosclerosis, we obtained comprehensive transcriptome maps of circulating immune cells (peripheral blood mononuclear cells, PBMCs) of early onset MI patients. One lncRNA significantly suppressed in post-MI patients was further investigated in a murine knockout model.METHODS AND RESULTS: Individual RNA-sequencing (RNA-seq) was conducted on PBMCs from 28 post-MI patients with a history of MI at age ≤50 years and stable disease ≥3 months before study participation, and from 31 healthy individuals without manifest cardiovascular disease or family history of MI as controls. RNA-seq revealed deregulated protein-coding transcripts and lncRNAs in post-MI PBMCs, among which nuclear enriched abundant transcript (NEAT1) was the most highly expressed lncRNA, and the only one significantly suppressed in patients. Multivariate statistical analysis of validation cohorts of 106 post-MI patients and 85 controls indicated that the PBMC NEAT1 levels were influenced (P = 0.001) by post-MI status independent of statin intake, left ventricular ejection fraction, low-density lipoprotein or high-density lipoprotein cholesterol, or age. We investigated NEAT1-/- mice as a model of NEAT1 deficiency to evaluate if NEAT1 depletion may directly and causally alter immune regulation. RNA-seq of NEAT1-/- splenocytes identified disturbed expression and regulation of chemokines/receptors, innate immunity genes, tumour necrosis factor (TNF) and caspases, and increased production of reactive oxygen species (ROS) under baseline conditions. NEAT1-/- spleen displayed anomalous Treg and TH cell differentiation. NEAT1-/- bone marrow-derived macrophages (BMDMs) displayed altered transcriptomes with disturbed chemokine/chemokine receptor expression, increased baseline phagocytosis (P < 0.0001), and attenuated proliferation (P = 0.0013). NEAT1-/- BMDMs responded to LPS with increased (P < 0.0001) ROS production and disturbed phagocytic activity (P = 0.0318). Monocyte-macrophage differentiation was deregulated in NEAT1-/- bone marrow and blood. NEAT1-/- mice displayed aortic wall CD68+ cell infiltration, and there was evidence of myocardial inflammation which could lead to severe and potentially life-threatening structural damage in some of these animals.CONCLUSION: The study indicates distinctive alterations of lncRNA expression in post-MI patient PBMCs. Regarding the monocyte-enriched NEAT1 suppressed in post-MI patients, the data from NEAT1-/- mice identify NEAT1 as a novel lncRNA-type immunoregulator affecting monocyte-macrophage functions and T cell differentiation. NEAT1 is part of a molecular circuit also involving several chemokines and interleukins persistently deregulated post-MI. Individual profiling of this circuit may contribute to identify high-risk patients likely to benefit from immunomodulatory therapies. It also appears reasonable to look for new therapeutic targets within this circuit.
KW - Adult
KW - Age of Onset
KW - Animals
KW - Case-Control Studies
KW - Cell Differentiation
KW - Cells, Cultured
KW - Chemokines/genetics
KW - Down-Regulation
KW - Female
KW - Humans
KW - Immunity, Innate
KW - Leukocytes, Mononuclear/immunology
KW - Macrophages/immunology
KW - Male
KW - Mice, Knockout
KW - Middle Aged
KW - Myocardial Infarction/genetics
KW - RNA, Long Noncoding/genetics
KW - Reactive Oxygen Species/metabolism
KW - Signal Transduction
KW - Spleen/immunology
KW - T-Lymphocytes, Helper-Inducer/immunology
KW - T-Lymphocytes, Regulatory/immunology
KW - Time Factors
U2 - 10.1093/cvr/cvz085
DO - 10.1093/cvr/cvz085
M3 - SCORING: Journal article
C2 - 30924864
VL - 115
SP - 1886
EP - 1906
JO - CARDIOVASC RES
JF - CARDIOVASC RES
SN - 0008-6363
IS - 13
ER -