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Objective: The purpose of this study was to explore the role of long noncoding RNA (lncRNA) prostate cancer antigen 3 (PCA3) in atherosclerosis and the underlying mechanism., Methods: The Gene Expression Omnibus (GEO) datasets were used to divide differentially expressed lncRNAs, microRNAs (miRNAs), and mRNAs. The expression of PCA3, miR-140-5p, RFX7 and ABCA1 were determined by qPCR or Western blot in ox-LDL-treated macrophages. Macrophage lipid accumulation s was evaluated using the Oil Red O staining and high-performance liquid chromatography. Target relationships among PCA3, miR-140-5p, RFX7, and ABCA1 promoter area were validated via dual-luciferase reporter gene assay or chromatin immunoprecipitation assay. The apoE -/- mouse model in vivo was designed to evaluate the effect of PCA3 on the reverse cholesterol transport (RCT) and atherosclerosis., Results: PCA3 was down-regulated in foam cells, whereas miR-140-5p was highly expressed. Overexpression of PCA3 promoted ABCA1-mediated cholesterol efflux and reduced lipid accumulation in macrophages. Besides, RFX7 bound to the ABCA1 promoter and increased ABCA1 expression. Targeted relationships and interactions on the expression between miR-140-5p and PCA3 or RFX7 were elucidated. PCA3 up-regulated ABCA1 expression by binding to miR-140-5p to up-regulate RFX7 and ABCA1 expression in macrophages. PCA3 promoted RCT and impeded the progression of atherosclerosis by sponging miR-140-5p in apoE -/- mice. Meanwhile, miR-140-5p also inhibit ABCA1 expression via downregulation of RFX7 to impede RCT and aggravate atherosclerosis., Conclusions: lncRNA PCA3 promotes ABCA1-mediated cholesterol efflux to inhibit atherosclerosis through sponging miR-140-5p and up-regulating RFX7., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Myocardin (MYOCD) plays an important role in cardiovascular disease. However, its underlying impact on atherosclerosis remains to be elucidated. ATP binding cassette transporter A1 (ABCA1), a key membrane-associated lipid transporter which maintains intracellular lipid homeostasis, has a protective function in atherosclerosis progress. The purpose of this study was to investigate whether and how the effect of MYOCD on atherosclerosis is associated with ABCA1 in vascular smooth muscle cells (VSMCs). We found both MYOCD and ABCA1 expression were dramatically decreased in atherosclerotic patient aortas compared to control. MYOCD knockdown inhibited ABCA1 expression in human aortic vascular smooth muscle cells (HAVSMCs), leading to reduced cholesterol efflux and increased intracellular cholesterol contents. MYOCD overexpression exerted the opposite effect. Mechanistically, MYOCD regulates ABCA1 expression in an SRF-dependent manner. Consistently, apolipoprotein E-deficient mice treated with MYOCD shRNA developed more plaques in the aortic sinus, which is associated with reduced ABCA1 expression, increased cholesterol retention in the aorta, and decreased high-density lipoprotein cholesterol levels in the plasma. Our data suggest that MYOCD deficiency exacerbates atherosclerosis by downregulating ABCA1 dependent cholesterol efflux from VSMCs, thereby providing a novel strategy for the therapeutic treatment of atherosclerotic cardiovascular disease., (Copyright © 2020. Published by Elsevier B.V.)

Abstract: Lipid metabolism disorder and inflammatory response are considered to be the major causes of atherosclerogenesis. Astragalin, the most important functional component of flavonoid obtained from persimmon leaves, has the hypolipidemic effects. However, it is unknown, how astragalin protects against atherosclerosis. The aim of this study was to observe the effects of astragalin on cholesterol efflux and inflammatory response and to explore the underlying mechanisms. Our results showed that astragalin upregulated the expression of ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1), promoted cholesterol efflux, and suppressed foam cell formation. Inhibition of the PPARγ/LXRα pathway abrogated the promotive effects of astragalin on both transporter expression and cholesterol efflux. In addition, treatment of astragalin markedly decreased the secretion of inflammatory factors, including interleukin 6, monocyte chemotactic protein 1, tumor necrosis factor α, and interleukin 1β. Mechanistically, astragalin upregulated ABCA1 and ABCG1 expression, which in turn reduced TLR4 surface levels and inhibited NF-κB nuclear translocation. Consistently, astragalin reduced atherosclerotic plaque area in apoE-/- mice. Taken together, these findings suggest that astragalin protects against atherosclerosis by promoting ABCA1- and ABCG1-mediated cholesterol efflux and inhibiting proinflammatory mediator release., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

CXC chemokine ligand 12 (CXCL12) is a member of the CXC chemokine family and mainly acts on cell chemotaxis. CXCL12 also elicits a proatherogenic role, but the molecular mechanisms have not been fully defined yet. We aimed to reveal if and how CXCL12 promoted atherosclerosis via regulating lipid metabolism. In vitro, our data showed that CXCL12 could reduce ABCA1 expression, and it mediated cholesterol efflux from THP-1-derived macrophages to apoA-I. Data from the luciferase reporter gene and chromatin immunoprecipitation assays revealed that transcription factor 21 (TCF21) stimulated the transcription of ABCA1 via binding to its promoter region, which was repressed by CXCL12. We found that CXCL12 increased the levels of phosphorylated glycogen synthase kinase 3β (GSK3β) and the phosphorylation of β-catenin at the Thr120 position. Inactivation of GSK3β or β-catenin increased the expression of TCF21 and ABCA1. Further, knockdown or inhibition of CXC chemokine receptor 4 (CXCR4) blocked the effects of CXCL12 on TCF21 and ABCA1 expression and the phosphorylation of GSK3β and β-catenin. In vivo, the overexpression of CXCL12 in Apoe -/- mice via lentivirus enlarged the atherosclerotic lesion area and increased macrophage infiltration in atherosclerotic plaques. We further found that the overexpression of CXCL12 reduced the efficiency of reverse cholesterol transport and plasma HDL-C levels, decreased ABCA1 expression in the aorta and mouse peritoneal macrophages (MPMs), and suppressed cholesterol efflux from MPMs to apoA-I in Apoe -/- mice. Collectively, these findings suggest that CXCL12 interacts with CXCR4 and then activates the GSK-3β/β-catenin T120 /TCF21 signaling pathway to inhibit ABCA1-dependent cholesterol efflux from macrophages and aggravate atherosclerosis. Targeting CXCL12 may be a novel and promising strategy for the prevention and treatment of atherosclerotic cardiovascular diseases., (Copyright © 2019 Gao et al.)

Objective: Previous studies suggest that IL-8 has an important role in the regulation of cholesterol efflux, but whether miRNAs are involved in this process is still unknown. The purpose of this study is to explore whether IL-8 promotes cholesterol accumulation by enhancing miR-183 expression in macrophages and its underlying mechanism., Methods and Results: Treatment of THP-1 macrophage-derived foam cells with IL-8 decreased ABCA1 expression and cholesterol efflux. Using bioinformatics analyses and dual-luciferase reporter assays, we found that miR-183 was highly conserved during evolution and directly inhibited ABCA1 protein and mRNA expression by targeting ABCA1 3'UTR. MiR-183 directly regulated endogenous ABCA1 expression levels. Furthermore, IL-8 enhanced the expression of miR-183 and decrease ABCA1 expression. Cholesterol transport assays confirmed that IL-8 dramatically inhibited apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux by increasing miR-183 expression. In contrast, treatment with anti-IL-8 antibody reversed these effects., Conclusion: IL-8 enhances the expression of miR-183, which then inhibits ABCA1 expression and cholesterol efflux. Our studies suggest that the IL-8-miR-183-ABCA1 axis may play an intermediary role in the development of atherosclerosis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Tanshinone IIA (Tan IIA) and Omentin-1 have a protective role in the cardiovascular system. However, if and how Tan IIA and Omentin-1 regulate cholesterol metabolism in macrophages has not been fully elucidated., Objective: To investigate the possible mechanisms of Tan IIA and Omentin-1 on preventing macrophage cholesterol accumulation and atherosclerosis development., Methods: The effect of Tan IIA on the protein and mRNA levels of Omentin-1 and ATP-binding cassette transporter A1 (ABCA1) in macrophages was examined by Western blot and qRT-PCR assay, respectively. Cholesterol efflux was assessed by liquid scintillation counting (LSC). Cellular lipid droplet was measured by Oil Red O staining, and intracellular lipid content was detected by high performance liquid chromatography (HPLC). In addition, the serum lipid profile of apoE-/- mice was measured by enzymatic method. The size of atherosclerotic lesion areas and content of lipids and collagen in the aortic of apoE-/- mice were examined by Sudan IV, Oil-red O, and Masson staining, respectively., Results: Tan IIA up-regulated expression of Omentin-1 and ABCA1 in THP-1 macrophages, promoting ABCA1-mediated cholesterol efflux and consequently decreasing cellular lipid content. Consistently, Tan IIA increased reverse cholesterol transport in apoE-/- mice. Plasma levels of high-density lipoprotein cholesterol (HDL-C), ABCA1 expression and atherosclerotic plaque collagen content were increased while plasma levels of low-density lipoprotein cholesterol (LDL-C) and atherosclerotic plaque sizes were reduced in Tan IIA-treated apoE-/- mice. These beneficial effects were, however, essentially blocked by knockdown of Omentin-1., Conclusion: Our results revealed that Tan IIA promotes cholesterol efflux and ameliorates lipid accumulation in macrophages most likely via the Omentin-1/ABCA1 pathway, reducing the development of aortic atherosclerosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Aims: Recent studies have suggested that heat shock protein 70 (HSP70) may play critical roles in cardiovascular disease. However, the effects of HSP70 on the development of atherosclerosis in apoE -/- mice remain largely unknown. This study was to investigate the role and potential mechanism of HSP70 in atherosclerosis., Methods: HSP70 was overexpressed in apoE -/- mice and THP-1-derived macrophages with lentiviral vectors. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaque in apoE -/- mice fed the Western type diet. Moreover, immunostaining was employed to detect the expression of relative proteins in aortic sinus. Reporter gene and chromatin immunoprecipitation were performed to analyze the effect of Elk-1 on the promoter activity of ABCA1 and ABCG1; [ 3 H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT)., Results: Our results showed that HSP70 increased lipid accumulation in arteries and promoted the formation of atherosclerotic lesion. The capacity of cholesterol efflux was reduced in peritoneal macrophages isolated from HSP70-overexpressed apoE -/- mice. The levels of ABCA1 and ABCG1 expression were also reduced in the peritoneal macrophages and the aorta from apoE -/- mice in response to HSP70. The c-Jun N-terminal kinase (JNK) and ETS transcription factor (Elk-1) played a critical role in HSP70-induced downregulation ABCA1 and ABCG1. Further, HSP70 reduced RCT from macrophages to plasma, liver, and feces in apoE -/- mice., Conclusions: HSP70 promotes the progression of atherosclerosis in apoE -/- mice by suppressing the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway., (Copyright © 2018 Elsevier B.V. All rights reserved.)

It was reported that puerarin decreases the total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and increases high-density lipoprotein cholesterol (HDL-C) level, but the underlying mechanism is unclear. This study was designed to determine whether puerarin decreased lipid accumulation via up-regulation of ABCA1-mediated cholesterol efflux in THP-1 macrophage-derived foam cells. Our results showed that puerarin significantly promoted the expression of ATP-binding cassette transporter A1 (ABCA1) mRNA and protein via the AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor gamma (PPARγ)-liver X receptor-alpha (LXR-α) pathway and decreased cellular lipid accumulation in human THP-1 macrophage-derived foam cells. The miR-7 directly targeted 3' untranslated region of STK11 (Serine/Threonine Kinase 11), which activated the AMPK pathway. Transfection with miR-7 mimic significantly reduced STK11 expression in puerarin-treated macrophages, decreased the phosphorylation of AMPK, down-regulated the expression of the PPARγ-LXR-α-ABCA1 expression. Additionally, treatment with miR-7 decreased cholesterol efflux and increased cholesterol levels in THP-1 macrophage-derived foam cells. Our study demonstrates that puerarin promotes ABCA1-mediated cholesterol efflux and decreases intracellular cholesterol levels through the pathway involving miR-7, STK11, and the AMPK-PPARγ-LXR-α-ABCA1 cascade., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rationale: Previous studies have shown that apolipoprotein-1 (apoA-1) binding protein (AIBP) is highly associated with the regulation of apoA-1 metabolism, suggesting its role in the treatment of atherosclerosis. However, how AIBP regulates foam cell formation remains largely unexplored., Objective: To investigate the mechanisms underlying AIBP inhibition of foam cell formation from macrophages., Methods and Results: THP-1-derived macrophages were incubated without or with apoA-1 and AIBP, followed by assessing the formation of foam cells and the potential mechanisms. Our results showed that AIBP and apoA-1 enhanced cholesterol efflux, altered the levels of cellular free cholesterol and cholesterol ester and prevented lipid accumulation so as to reduce the formation of foam cells. Meanwhile, lack of AIBP 115-123 amino acids resulted in the loss of AIBP binding to apoA-1. Moreover, our chemiluminescent analysis showed that AIBP promoted biotin-labeled apoA-1 binding to macrophages. Besides with AIBP, more apoA-1 bound to ABCA1, a key transporter responsible for cholesterol efflux to apoA-1, as indicated by our co-immunoprecipitation assay. Our results also showed that AIBP did not regulate ABCA1 mRNA expression, but stabilized its protein from CSN2-mediated degradation., Conclusions: AIBP promotes apoA-1 binding to ABCA1 on the cell membrane of macrophages and prevents ABCA1 protein from CSN2-mediated degradation so as to prevent foam cell formation. AIBP 115-123 amino acids is at least partially responsible for its binding to apoA-1., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

This study was designed to evaluate whether CSE/H2S system, which is regulated by miR-216a, regulated ABCA1-mediated cholesterol efflux and cholesterol contents in THP-1 macrophages-derived foam cells. Our qPCR and western blotting results showed that CSE/H2S significantly up-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) mRNA and protein via PI3K/AKT pathway in foam cells derived from human THP-1 macrophages. The miR-216a directly targeted 3' untranslated region of CSE. It significantly reduced CSE and ABCA1 expression, and also decreased the phosphorylation of PI3K and AKT. Additionally, cholesterol efflux decreased, and cholesterol levels increased in THP-1 macrophage-derived foam cells in response to treatment with miR-216a. Our study demonstrates that CSE/H2S system is regulated by miR-216a, and regulates ABCA1-mediated cholesterol efflux and cholesterol levels through the PI3K/AKT pathway., (Copyright © 2016 Elsevier Inc. All rights reserved.)