LncRNA MALAT1 Enhances ox-LDL-Induced Autophagy through the SIRT1/MAPK/NF-κB Pathway in Macrophages

2020 ◽  
Vol 18 (6) ◽  
pp. 652-662 ◽  
Author(s):  
Jiaqi Yang ◽  
Xuze Lin ◽  
Liangshan Wang ◽  
Tienan Sun ◽  
Qi Zhao ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Foam Cell ◽  
Cell Model ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cerebrovascular Diseases ◽  
Sirtuin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Atherosclerosis is the main cause of cardiovascular and cerebrovascular diseases. In advanced atherosclerotic plaque, macrophage apoptosis coupled with inflammatory cytokine secretion promotes the formation of necrotic cores. It has also been demonstrated that the long-noncoding Ribonucleic Acid (lnc RNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), with its potent function on gene transcription modulation, maintains oxidized low-density lipoprotein (ox-LDL)- induced macrophage autophagy (i.e., helps with cholesterol efflux). It also showed that MALAT1 activated Sirtuin 1 (SIRT1), which subsequently inhibited the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways. ox-LDL has been used to incubate human myeloid leukemia mononuclear cells (THP-1)-derived macrophages to establish an in vitro foam cell model. Quantitative reverse-transcription polymerase chain reaction and Western blot analyses confirmed the increased expression level of MALAT1 and the autophagy-related protein Microtubuleassociated protein light chain 3 (LC-3), beclin-1. The small interfering RNA study showed a significant decrease in autophagy activity and an increase in apoptotic rate when knocking down MALAT1. Further study demonstrated that MALAT1 inhibited the expression of MAPK and NF-κB (p65) by upregulating SIRT1.

Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

Curcumin improves atherosclerosis by inhibiting the epigenetic repression of lncRNA MIAT to miR-124

Vascular ◽  
2022 ◽  
pp. 170853812110409
Author(s):  
Shang Ouyang ◽  
Ou Zhang ◽  
Hua Xiang ◽  
Yuan-Hui Yao ◽  
Zhi-Yong Fang
Keyword(s):  
Myocardial Infarction ◽  
Cell Apoptosis ◽  
Cell Model ◽  
Umbilical Vein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Umbilical Vein Endothelial Cells

Objectives: Atherosclerosis is a dominant cardiovascular disease. Curcumin has protective effect on atherosclerosis. However, the mechanisms remain to be explored. Methods: Atherosclerosis was induced by feeding mice with high-fat diet (HFD) and ox-low-density lipoprotein (LDL)-induced human umbilical vein endothelial cells (HUVECs) were structured. Oil Red O staining was used to evaluate the plaques in the artery. Quantitative real-time PCR (qRT-PCR) was conducted to detect the level of myocardial infarction associated transcript (MIAT), miR-124, and enhancer of zeste homolog 2 (EZH2). We performed western blotting and enzyme linked immunosorbent assay to examine the expression of EZH2 and cytokines including IL-1β, TNFα, IL-6, and IL-8, respectively. RNA immunoprecipitation and chromatin immunoprecipitation (ChIP) were used to validate the interaction between myocardial infarction associated transcript and EZH2. Flow cytometry and CCK-8 assay were used to examine cell apoptosis and proliferation, respectively. Results: Curcumin suppressed inflammation in atherosclerosis mouse model and ox-LDL-induced cell model. MIAT overexpression and miR-124 inhibition relieved the anti-inflammation effect of curcumin in ox-LDL-induced cell. MIAT regulated miR-124 by interacting with EZH2. Curcumin relieved ox-LDL-induced cell inflammation via regulating MIAT/miR-124 pathway. Conclusion: MIAT/miR-124 axis mediated the effect of curcumin on atherosclerosis and altered cell apoptosis and proliferation, both in vivo and in vitro. These data further support the application of curcumin in control of atherosclerosis advancement.

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