期刊：
Advances in Clinical Chemistry,2015年70:1-30 ISSN：0065-2423
通讯作者：
Tang, Chao-Ke
作者机构：
[Tang, Chao-Ke; Yu, Xiao-Hua] Univ South China, Key Lab Atherosclerol Hunan Prov, Mol Target New Drug Discovery & Cooperat Innovat, Life Sci Res Ctr, Hengyang, Peoples R China.;[Zheng, Xi-Long] Univ Calgary, Hlth Sci Ctr, Cumming Sch Med, Dept Biochem & Mol Biol,Libin Cardiovasc Inst Alb, Calgary, AB, Canada.
通讯机构：
[Tang, Chao-Ke] U;Univ South China, Key Lab Atherosclerol Hunan Prov, Mol Target New Drug Discovery & Cooperat Innovat, Life Sci Res Ctr, Hengyang, Peoples R China.
作者机构：
[Zhang, Min; Liu, Dan; Tang, Chao-ke; Tan, Yu-lin; Lv, Yun-cheng; Li, Liang; He, Ping-ping; Xie, Wei; Tang, Yan-yan; Ouyang, Xin-ping; Yao, Feng] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan,Prov Life Sci Res Ctr, Hengyang 421001, Hunan, Peoples R China.;[Lv, Yun-cheng; Xie, Wei] Univ South China, Lab Clin Anat, Hengyang 421001, Hunan, Peoples R China.;[Yang, Jing] Univ South China, Dept Endocrinol & Metab, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.;[Yao, Feng] Univ South China, Dept Lab Anim Sci, Hengyang 421001, Hunan, Peoples R China.;[Cayabyab, Francisco S.] Univ Saskatchewan, Coll Med, Dept Surg, Saskatoon, SK S7N 0W0, Canada.
通讯机构：
[Tang, Chao-ke] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan,Prov Life Sci Res Ctr, Hengyang 421001, Hunan, Peoples R China.
关键词：
ABCA1;Atherosclerosis;Cholesterol efflux;Diosgenin;Macrophage foam cells;Reverse cholesterol transport
摘要：
Rationale: Diosgenin (Dgn), a structural analogue of cholesterol, has been reported to have the hypolipidemic and antiatherogenic properties, but the underlying mechanisms are not fully understood. Given the key roles of macrophages in cholesterol metabolism and atherogenesis, it is critical to investigate macrophage cholesterol efflux and development of atherosclerotic lesion after Dgn treatment. Objective: This study was designed to evaluate the potential effects of Dgn on macrophage cholesterol metabolism and the development of aortic atherosclerosis, and to explore its underlying mechanisms. Methods and Results: Dgn significantly up-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) protein, but didn't affect liver X receptor a levels in foam cells derived from human THP-1 macrophages and mouse peritoneal macrophages (MPMs) as determined by western blotting. The miR-19b levels were markedly down-regulated in Dgn-treated THP-1 macrophages/MPM-derived foam cells. Cholesterol transport assays revealed that treatment with Dgn alone or together with miR-19b inhibitor notably enhanced ABCA1-dependent cholesterol efflux, resulting in the reduced levels of total cholesterol, free cholesterol and cholesterol ester as determined by high-performance liquid chromatography. The fecal H-3-sterol originating from cholesterol-laden MPMs was increased in apolipoprotein E knockout mice treated with Dgn or both Dgn and antagomiR-19b. Treatment with Dgn alone or together with antagomiR-19b elevated plasma high-density lipoprotein levels, but reduced plasma low-density lipoprotein levels. Accordingly, aortic lipid deposition and plaque area were reduced, and collagen content and ABCA1 expression were increased in mice treated with Dgn alone or together with antagomiR-19b. However, miR-19b overexpression abrogated the lipid-lowering and atheroprotective effects induced by Dgn. Conclusion: The present study demonstrates that Dgn enhances ABCA1-dependent cholesterol efflux and inhibits aortic atherosclerosis progression by suppressing macrophage miR-19b expression. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
摘要：
The lower hybrid wave current drive (LHCD) in the presence of magnetic islands in Tokamak plasma with the circular cross section is studied numerically. The emergence of magnetic island is considered as a perturbation characterized by the perturbed magnetic flux near the resonant surface. By taking the perturbed magnetic field into account in the lower hybrid simulation code, the wave propagation, power deposition, and current drive are investigated using typical Experimental Advanced Superconductor Tokamak (EAST) L-and H-modes discharge parameters. The simulation results show that the wave propagation, power deposition, and current drive are significantly affected by the existence of magnetic island. Due to the H-mode pedestal, the effect of magnetic islands on the LHCD in EAST H-mode discharge is more significant than that in the L-mode discharge. (C) 2014 AIP Publishing LLC.
作者机构：
[Xiong, Yan; Gong, Yong-Zhen] Cent S Univ, Sch Pharmaceut Sci, Dept Pharmacol, Changsha, Hunan, Peoples R China.;[Xiong, Yan] Guangzhou Med Univ, Sch Pharmaceut Sci, Guangzhou Res Inst Snake Venom, Guangzhou 510182, Guangdong, Peoples R China.;[Yuan, Hao-Yu; Liao, Duan-Fang; Sun, Shao-Wei; Yang, Xue-Feng] Univ South China, Life Sci Res Ctr, Inst Cardiovasc Dis, Hengyang, Peoples R China.;[Tan, Xi; Zheng, Xi-Long; Gong, Yong-Zhen; Tuo, Qin-Hui; Liao, Duan-Fang; Xie, Xue-Jiao; Sun, Shao-Wei] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha, Hunan, Peoples R China.;[Zheng, Xi-Long] Univ Calgary, Cumming Sch Med, Libin Cardiovasc Inst Alberta, Dept Biochem & Mol Biol, Calgary, AB, Canada.
通讯机构：
[Xiong, Yan] G;Guangzhou Med Univ, Sch Pharmaceut Sci, Guangzhou Res Inst Snake Venom, Guangzhou 510182, Guangdong, Peoples R China.
关键词：
Ezetimibe;Liver X receptor;Sterol-regulatory element binding protein 1;ATP-binding cassette transporter A1;Caveolin-1
摘要：
Background: Ezetimibe is a potent inhibitor of Niemann-Pick type C1-Like 1 and has been approved for the treatment of hypercholesterolemia. Our preliminary study showed that ezetimibe promotes cholesterol efflux from vascular smooth muscle cells (VSMCs). Our aim was to investigate the cellular mechanisms underlying the ezetimibe actions. Methods and Results: Rat VSMCs were converted to foam cells by incubation with cholesterol: methyl-beta-cyclodextrin. The intracellular free cholesterol, total cholesterol, and the ratio of cholesteryl ester to total cholesterol were decreased after the incubation of VSMCs with different concentrations of ezetimibe (3, 10, 30, and 30 mu mol/l) or treated with 30 mu mol/l of ezetimibe for different time periods (6, 12, 24, and 48 h). Our results also showed that the expression of caveolin-1, liver X receptor a, and ATP-binding cassette transporter ABCA1 was enhanced, but the expression of nSREBP-1c was decreased in a concentration- and time-dependent manner. RNA interference was used to determine the roles of caveolin-1 and SREBP-1 in the lipid-lowering effect of ezetimibe. The results showed that caveolin- 1 was involved in the regulation of intracellular cholesterol content, and the expression of caveolin-1 was repressed by SREBP-1. Conclusion: The present study indicates that ezetimibe protects VSMCs from cholesterol accumulation by regulating the expression of lipid metabolism-related genes. (C) 2014 S. Karger AG, Basel
摘要：
Rationale: Macrophage accumulation of cholesterol leads to foam cell formation which is a major pathological event of atherosclerosis. Recent studies have shown that microRNA (miR)-19b might play an important role in cholesterol metabolism and atherosclerotic diseases. Here, we have identified miR-19b binding to the 3'UTR of ATP-binding cassette transporter A1 (ABCA1) transporters, and further determined the potential roles of this novel interaction in atherogenesis. Objective: To investigate the molecular mechanisms involved in a miR-19b promotion of macrophage cholesterol accumulation and the development of aortic atherosclerosis. Methods and results: We performed bioinformatics analysis using online websites, and found that miR-19b was highly conserved during evolution and directly bound to ABCA1 mRNA with very low binding free energy. Luciferase reporter assay confirmed that miR-19b bound to 3110-3116 sites within ABCA1 3'UTR. MiR-19b directly regulated the expression levels of endogenous ABCA1 in foam cells derived from human THP-1 macrophages and mouse peritoneal macrophages (MPMs) as determined by qRT-PCR and western blot. Cholesterol transport assays revealed that miR-19b dramatically suppressed apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux, resulting in the increased levels of total cholesterol (TC), free cholesterol (FC) and cholesterol ester (CE) as revealed by HPLC. The excretion of H-3-cholesterol originating from cholesterol-laden MPMs into feces was decreased in mice overexpressing miR-19b. Finally, we evaluated the proatherosclerotic role of miR-19b in apolipoprotein E deficient (apoE(-/-)) mice. Treatment with miR-19b precursor reduced plasma high-density lipoprotein (HDL) levels, but increased plasma low-density lipoprotein (LDL) levels. Consistently, miR-19b precursor treatment increased aortic plaque size and lipid content, but reduced collagen content and ABCA1 expression. In contrast, treatment with the inhibitory miR-19b antisense oligonucleotides (ASO) prevented or reversed these effects. Conclusion: MiR-19b promotes macrophage cholesterol accumulation, foam cell formation and aortic atherosclerotic development by targeting ABCA1. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
摘要：
Objectives: ATP-binding cassette transporter A1 (ABCA1) is critical in exporting cholesterol from macrophages and plays a protective role in the development of atherosclerosis. This study was to determine the effects and potential mechanisms of Chlamydia pneumoniae (C. pneumoniae) on ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells. Methods and results: C. pneumoniae significantly decreased the expression of ABCA1 and reduced cholesterol efflux. Furthermore, we found that C. pneumoniae suppressed ABCA1 expression via upregulation of miR-33s. The inhibition of C. pneumoniae-induced NF-kappa B activation decreased miR-33s expression and enhanced ABCA1 expression. In addition, C. pneumoniae increased Toll-like receptor 2 (TLR2) expressions, inhibition of which by siRNA could also block NF-kappa B activation and miR-33s expression, and promot the expression of ABCA1. Conclusion: Taken together, these results reveal that C. pneumoniae may negatively regulate ABCA1 expression via TLR2-NF-kappa B and miR-33 pathways in THP-1 macrophage-derived foam cells, which may provide new insights for understanding the effects of C. pneumoniae on the pathogenesis of atherosclerosis. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
摘要：
Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and responsible for catalyzing lipolysis of triglycerides in lipoproteins. LPL is produced mainly in adipose tissue, skeletal and heart muscle, as well as in macrophage and other tissues. After synthesized, it is secreted and translocated to the vascular lumen. LPL expression and activity are regulated by a variety of factors, such as transcription factors, interactive proteins and nutritional state through complicated mechanisms. LPL with different distributions may exert distinct functions and have diverse roles in human health and disease with close association with atherosclerosis. It may pose a pro-atherogenic or an anti-atherogenic effect depending on its locations. In this review, we will discuss its gene, protein, synthesis, transportation and biological functions, and then focus on its regulation and relationship with atherosclerosis and potential underlying mechanisms. The goal of this review is to provide basic information and novel insight for further studies and therapeutic targets. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
摘要：
Background:Both clinical data and basic science studies suggest that advanced oxidation protein products (AOPPs) may contribute to the progression of atherosclerosis. The aim of this study was to investigate the effects of AOPPs on ATP-binding cassette transporter (ABC) A1 and ABCG1 expression, lipid accumulation and atherosclerotic lesions in apolipoprotein E knockout (apoE-KO) mice.Methods and Results:Male 8-week-old apoE-KO mice were fed a high-fat/high-cholesterol diet. Mice received intraperitoneal injections of AOPPs (5 mg/kg) and/or Janus Kinase (JAK) inhibitor AG-490 (5 mg/kg) once every other day for 8 weeks. As shown in our data, AOPPs increased lipid levels of plasma, and promoted advanced lesions in the aortic regions in apoE-KO mice. The ABCA1, ABCG1 and liver X receptor alpha (LXRα) expression were downregulated in apoE-KO mice treated with AOPPs, whereas the lesions in the aortas were decreased, and the ABCA1, ABCG1 and LXRα expression were upregulated in mice treated with AOPPs plus AG-490, compared to the mice treated with AOPPs only. The ABCA1 and LXRα expressions of aortas, liver and intestine were downregulated in the AOPPs group, while the expressions were upregulated in the AOPPs-plus-AG-490 group when compared to the AOPPs group. The same results can be also observed in peritoneal macrophages.Conclusions:AOPPs increase accumulation of lipids and exacerbate atherosclerosis through downregulation of ABCA1 and ABCG1 expression, and the JAK-LXRα signaling pathway in apoE-KO mice. (Circ J 2014; 78: 2760–2770)
摘要：
Rationale: Macrophage cholesterol homeostasis maintenance is the result of a balance between influx, endogenous synthesis, esterification/hydrolysis and efflux. Excessive accumulation of cholesterol leads to foam cell formation, which is the major pathology of atherosclerosis. Previous studies have shown that miR-27 (miR-27a and miR-27b) may play a key role in the progression of atherosclerosis. Objective: We set out to investigate the molecular mechanisms of miR-27a/b in intracellular cholesterol homeostasis. Methods and results: In the present study, our results have shown that the miR-27 family is highly conserved during evolution, present in mammals and directly targets the 3' UTR of ABCA1, LPL, and ACAT1. apoA1, ABCG1 and SR-B1 lacking miR-27 bind sites should not be influenced by miR-27 directly. miR-27a and miR-27b directly regulated the expression of endogenous ABCA1 in different cells. Treatment with miR-27a and miR-27b mimics reduced apoA1-mediated cholesterol efflux by 33.08% and 44.61% in THP-1 cells, respectively. miR-27a/b also regulated HDL-mediated cholesterol efflux in THP-1 macrophages and affected the expression of apoA1 in HepG2 cells. However, miR-27a/b had no effect on total cellular cholesterol accumulation, but regulated the levels of cellular free cholesterol and cholesterol ester. We further found that miR-27a/b regulated the expression of LPL and CD36, and then affected the ability of THP-1 macrophages to uptake Dil-oxLDL. Finally, we identified that miR-27a/b regulated cholesterol ester formation by targeting ACAT1 in THP-1 macrophages. Conclusion: These findings indicate that miR-27a/b affects the efflux, influx, esterification and hydrolysis of cellular cholesterol by regulating the expression of ABCA1, apoA1, LPL, CD36 and ACAT1. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
