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

Abstract

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.

Long noncoding RNA NEAT1 correlates with higher disease risk, worse disease condition, decreased miR‐124 and miR‐125a and predicts poor recurrence‐free survival of acute ischemic stroke

“…In clinical practice, only a few studies explore the role of lncRNA NEAT1 in disease risk or disease condition of cardiovascular and cerebrovascular diseases or other inflammatory disease . For example, lncRNA NEAT1 has been found to be overexpressed in post‐myocardial infarction patients and patients with tuberculosis, indicating that lncRNA NEAT1 may act as a biomarker for increased risk of these diseases .…”

“…13,21 For example, lncRNA NEAT1 has been found to be overexpressed in post-myocardial infarction patients and patients with tuberculosis, indicating that lncRNA NEAT1 may act as a biomarker for increased risk of these diseases. 12,13 For the disease condition or inflammation, a study displays that lncRNA NEAT1 expression is associated with left ventricular ejection fraction, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol in post-myocardial infarction patients. 13 And, another study shows that lncRNA NEAT1 expression is positively associated with Acute Physiology and Chronic Health Evaluation (APACHE) II score, TNF-α, IL-1β, IL-6, and IL-8, but is negatively correlated with IL-10 in sepsis patients.…”

“…12,13 For the disease condition or inflammation, a study displays that lncRNA NEAT1 expression is associated with left ventricular ejection fraction, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol in post-myocardial infarction patients. 13 And, another study shows that lncRNA NEAT1 expression is positively associated with Acute Physiology and Chronic Health Evaluation (APACHE) II score, TNF-α, IL-1β, IL-6, and IL-8, but is negatively correlated with IL-10 in sepsis patients. 21 These data suggest that lncRNA NEAT1 may positively correlate with disease severity and inflammation level in cardiovascular and cerebrovascular diseases as well as inflammatory disease.…”

“…Long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1), which is an lncRNA that is essential for the formation of paraspeckles and interacts with many intracellular regulatory factors, has been widely investigated in the cancer field . Recently, some studies have revealed that lncRNA NEAT1 is overexpressed in myocardial infarction patients and tuberculosis patients . Furthermore, the biological roles of lncRNA NEAT1 in cardiovascular and cerebrovascular diseases have been disclosed in some experiments, such as the promotion of lncRNA NEAT1 on inflammatory response in myocardial ischemia‐reperfusion injury mice models and the inhibition of lncRNA NEAT1 knockdown on atherosclerosis‐correlated events in vitro .…”

“…[9][10][11] Recently, some studies have revealed that lncRNA NEAT1 is overexpressed in myocardial infarction patients and tuberculosis patients. 12,13 Furthermore, the biological roles of lncRNA NEAT1 in cardiovascular and cerebrovascular diseases have been disclosed in some experiments, such as the promotion of lncRNA NEAT1 on inflammatory response in myocardial ischemia-reperfusion injury mice models and the inhibition of lncRNA NEAT1 knockdown on atherosclerosis-correlated events in vitro. 14,15 For stroke, previous study displays that lncRNA NEAT1 facilitates oxygen-glucose deprivation/reoxygenation (OGD/R) injury and neuroinflammation damage of microglial cells, meanwhile, lncRNA NEAT1 enhances intima thickening or vascular occlusion through modulating the phenotype conversion of vascular smooth muscle cells, together with excessive apoptosis of epithelial cells, indicating that lncRNA NEAT1 is a therapeutic target for ischemic stroke.…”