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.
作者机构:
[L(U) Yun-cheng; TANG Yan-yan; ZHAO Guo-jun; YAO Feng; XIE Wei; OU-YANG Xin-ping; JUAN Peng; ZHANG Min; LIU Dan; TANG Chao-ke] Institute of Cardiovascular Research,Life Science Research Center,University of South China,Hengyang 421001,China;[L(U) Yun-cheng; XIE Wei] Laboratory of Clinical Anatomy,University of South China,Hengyang 421001,China
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:
Institute of Cardiovascular Research,Key Laboratory for Atherosclerology of Hunan Province,Life Science Research Center,University of South China
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
作者机构:
[Guojun Zhao] Department of Histology and Embryology, Guilin Medical University, Guilin, Guangxi 541004, China;[Zhongcheng Mo; Chaoke Tang] Institute of Cardiovascular Research, Life Science Research Center,University of South China, Hengyang, 421001, China
会议名称:
The 18th Congress of the International Federation of Associations of Anatomists (IFAA)(第十八届国际解剖学家协会联合大会)
会议时间:
2014-8-8
会议地点:
北京
会议主办单位:
中国解剖学会
会议论文集名称:
The 18th Congress of the International Federation of Associations of Anatomists (IFAA)(第十八届国际解剖学家协会联合大会)论文集
摘要:
<正>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 C.pneumoniae on cellular cholesterol efflux in THP-1 macrophage-derived foam cells.C.pneumoniae significantly decreased cholesterol efflux and
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.