作者机构：
[Tang, Dan; Ou, Weiwei; Wang, Deming; Chen, Quan; Wang, Jiazheng; Xiao, Ji] Univ South China, Affiliated Hosp 2, Dept Anesthesiol, Hengyang 421001, Peoples R China.;[Mo, Zhongcheng] Univ South China, Dept Histol & Embryol, Hengyang 421001, Peoples R China.;[Tang, Chaoke] Univ South China, Inst Cardiovasc Res, Life Sci Res Ctr, Key Lab Atherosclerol Hunan Prov, Hengyang 421001, Peoples R China.;[Peng, Liangyu] Univ South China, Affiliated Hosp 1, Dept Anesthesiol, Hengyang 421001, Peoples R China.
通讯机构：
[Wang, Deming; Peng, Liangyu] U;Univ South China, Affiliated Hosp 2, Dept Anesthesiol, Hengyang 421001, Peoples R China.;Univ South China, Affiliated Hosp 1, Dept Anesthesiol, Hengyang 421001, Peoples R China.
关键词：
liver X receptor;cytokine;mRNA decay;tristetraprolin;mitogen-activated protein kinase
摘要：
Liver X receptors (LXRs) have anti-inflammatory properties. Whether LXRs play a role in post-transcriptional control of inflammatory cytokine expression is not clear. Here, we firstly identified that the synthetic LXR agonist T0901317 promoted IL-1β, IL-6 and TNFa mRNA degradation. Moreover, T0901317 destabilized TNFa mRNA through its 3'-untranslated region. In addition, T0901317 increased the expression of tristetraprolin (TTP), while antagonizing TTP with siRNA abrogated T0901317-mediated inflammatory cytokine mRNA decay. Interestingly, T0901317 repressed LPS-induced phosphorylation of ERK1/2 and p38 mitogen-activated protein kinase (MAPK) in THP-1 macrophages. The evidence presented here confirms that LXR activation with T0901317 inhibits the phosphorylation of ERK1/2 and p38 MAPK, likely resulting in the increased expression of TTP and the decay of LPS-induce inflammatory cytokine mRNAs.
作者机构：
[王程] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China;[王程] Department of Spine Surgery, the First Affiliated Hospital, University of South China, Hengyang 421001, China;[王文军; 晏怡果; 杨威] Department of Spine Surgery, the First Affiliated Hospital, University of South China, Hengyang 421001, China;[于小华] Life Science Research Center, University of South China, Hengyang 421001, China;[张健] Department of Hand and Micro-surgery, the First Affiliated Hospital, University of South China, Hengyang 421001, China
期刊：
Journal of Physiology and Biochemistry,2016年72(4):657-667 ISSN：1138-7548
通讯作者：
Yi, Guang-Hui
作者机构：
[Jiang, Yue; Peng, Xiao-Shan; Liu, Xing; Ren, Kun; Yi, Guang-Hui; Suo, Rong; Tang, Zhen-Li] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, 28 W Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;[Xiong, Sheng-Lin] You Country Peoples Hosp, Zhuzhou 412300, Hunan, Peoples R China.;[Zhang, Qing-Hai] Univ South China, Affiliated Hosp 1, Clin Res Inst, Hengyang 421001, Hunan, Peoples R China.;[Mo, Zhong-Cheng] Univ South China, Inst Cardiovasc Res, Life Sci Res Ctr, Key Lab Atherosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Yi, Guang-Hui] U;Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, 28 W Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.
关键词：
S1P;SR-BI;ABCA1;SphK;S1P receptors;Release
摘要：
Sphingosine-1-phosphate (S1P), which has emerged as a pivotal signaling mediator that participates in the regulation of multiple cellular processes, is derived from various cells, including vascular endothelial cells. S1P accumulates in lipoproteins, especially HDL, and the majority of free plasma S1P is bound to HDL. We hypothesized that HDL-associated S1P is released through mechanisms associated with the HDL maturation process. ApoA-I, a major HDL apolipoprotein, is a critical factor for nascent HDL formation and lipid trafficking via ABCA1. Moreover, apoA-I is capable of promoting bidirectional lipid movement through SR-BI. In the present study, we confirmed that apoA-I can facilitate the production and release of S1P by HUVECs. Furthermore, we demonstrated that ERK1/2 and SphK activation induced by apoA-I is involved in the release of S1P from HUVECs. Inhibitor and siRNA experiments showed that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I. However, the effects triggered by apoA-I were not suppressed by inhibiting ABCA1/JAK2 or the SR-BI/Src pathway. S1P released due to apoA-I activation can stimulate the (ERK1/2)/SphK1 pathway through S1PR (S1P receptor) 1/3. These results indicated that apoA-I not only promotes S1P release through ABCA1 and SR-BI but also indirectly activates the (ERK1/2)/SphK1 pathway by releasing S1P to trigger their receptors. In conclusion, we suggest that release of S1P induced by apoA-I from endothelial cells through ABCA1 and SR-BI is a self-positive-feedback process: apoA-I-(ABCA1 and SR-BI)-(S1P release)-S1PR-ERK1/2-SphK1-(S1P production)-(more S1P release induced by apoA-I).
期刊：
Advances in Clinical Chemistry,2015年71:171-203 ISSN：0065-2423
通讯作者：
Tang, Chao-Ke
作者机构：
[Tang, Chao-Ke; Yu, Xiao-Hua] Univ South China, Life Sci Res Ctr, Key Lab Atherosclerol Hunan Prov, Mol Target New Drug Discovery & Cooperat Innovat, Hengyang, Peoples R China.;[Zheng, Xi-Long] Univ Calgary, Hlth Sci Ctr, Dept Biochem & Mol Biol, Libin Cardiovasc Inst Alberta,Cumming Sch Med, Calgary, AB, Canada.
通讯机构：
[Tang, Chao-Ke] U;Univ South China, Life Sci Res Ctr, Key Lab Atherosclerol Hunan Prov, Mol Target New Drug Discovery & Cooperat Innovat, Hengyang, Peoples R China.
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.
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.
