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LncRNA MALAT1 Enhances ox-LDL-Induced Autophagy through the SIRT1/MAPK/NF-κB Pathway in Macrophages
Jiaqi Yang1, Xuze Lin1, Liangshan Wang2
1Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Abstract:
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.
Insights
Long-noncoding RNA MALAT1 promotes macrophage autophagy and cholesterol efflux in atherosclerosis by activating SIRT1, thereby inhibiting inflammatory pathways and reducing cell death.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Cell Biology
Background:
- Atherosclerosis pathogenesis involves macrophage apoptosis and inflammation, leading to necrotic core formation.
- Oxidized low-density lipoprotein (ox-LDL) induces foam cell formation, a key event in atherosclerotic plaque development.
- Long non-coding RNAs (lncRNAs) play crucial roles in regulating cellular processes relevant to disease.
Purpose of the Study:
- To investigate the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in ox-LDL-induced macrophage responses.
- To elucidate the molecular mechanisms by which MALAT1 influences autophagy, apoptosis, and inflammatory signaling in macrophages.
Main Methods:
- Established an in vitro foam cell model using THP-1 derived macrophages incubated with ox-LDL.
- Utilized quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot to assess gene and protein expression.
- Employed small interfering RNA (siRNA) to knockdown MALAT1 and evaluate its functional impact on autophagy and apoptosis.
Main Results:
- MALAT1 expression was upregulated in ox-LDL-induced foam cells, along with autophagy markers (LC-3, beclin-1).
- Knockdown of MALAT1 significantly reduced autophagy activity and increased macrophage apoptosis.
- MALAT1 was found to upregulate Sirtuin 1 (SIRT1), which subsequently inhibited MAPK and NF-κB signaling pathways.
Conclusions:
- MALAT1 plays a protective role in the context of ox-LDL-induced macrophage injury by promoting autophagy and cholesterol efflux.
- MALAT1 exerts its effects via the SIRT1/MAPK/NF-κB signaling axis, offering a potential therapeutic target for atherosclerosis.
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