Send to

Choose Destination
Cardiovasc Res. 2019 Mar 29. pii: cvz085. doi: 10.1093/cvr/cvz085. [Epub ahead of print]

Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients.

Author information

Department of Cardiology, Campus Benjamin Franklin.
Berlin-Brandenburg Center for Regenerative Therapies (BCRT).
RNA Biology Laboratory, RIKEN Advanced Research Institute, Wako, Saitama, Japan.
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Institute for Cardiomyopathies, Department of Cardiology, University Hospital Heidelberg, Germany.
Site Heidelberg, German Center for Cardiovascular Research (DZHK).
Institute for Biometry and Clinical Epidemiology.
Berlin Institute of Health (BIH), Berlin, Germany.
Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
Site Hamburg/Lübeck/Kiel, German Center for Cardiovascular Research (DZHK).
Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Department of Genetics, Genome Technology Center, Stanford University Medical School, CA, USA.
German Center for Cardiovascular Research (DZHK), Site Berlin, Germany.
Institute of Cardiac Diagnostics and Therapy (IKDT), Berlin, Germany.



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 (PBMCs) of early onset MI patients. One lncRNA significantly suppressed in post-MI patients was further investigated in a murine knockout model.


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 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, LDL or HDL 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, 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.


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.


Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center