通讯机构：
[Tang, Chao-Ke] U;Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Hunan, Peoples R China.
关键词：
ATP-binding cassette transporter A1;Interleukin-12;Interleukin-18;Liver X receptor alpha;Nuclear factor-kappa B
摘要：
Background: Interleukin (IL)-18 and IL-12 synergize for the production of interferon (IFN)-γ, which can downregulate ATP-binding cassette transporter A1 (ABCA1) expression. The aim of the present study was to investigate the effect of IL-18 and/or IL-12 on ABCA1 expression. Methods and Results: IL-18 combined with IL-12 decreased ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells, whereas IL-18 or IL-12 alone had no effect. IL-12 increased IL-18 receptor (IL-18R) expression, which was suppressed by small interfering RNA (siRNA) for signal transducer and activator of transcription 3. IL-18R but not IL-12 receptor siRNA completely reversed the effects of IL-18 and IL-12 on ABCA1 expression and cellular cholesterol efflux. Treatment with IL-18 plus IL-12 markedly augmented nuclear translocation of nuclear factor (NF)-κB but had no effect on expression and activity of liver X receptor α. IL-18 and IL-12 also significantly increased zinc finger protein 202 (ZNF202) levels and IFN-γ secretion. Furthermore, siRNA for ZNF202 or IFN-γ significantly impaired IL-18/IL-12-induced suppression of ABCA1, whereas NF-κB siRNA treatment blocked IL-18/IL-12' action on ZNF202 levels, IFN-γ secretion, and ABCA1 expression. Conclusions: IL-18 and IL-12 together can decrease ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells through the IL-18R/NF-κB signaling pathway.
作者机构：
[Yu, Xiaohua; Zhao, Guojun; Yin, Kai; Li, Xiaoxu; Tang, Chaoke; Jiang, Zhisheng; Xiao, Ji; Mo, Zhongcheng] Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.;[Yu, Xiaohua] Univ S China, Sch Nursing, Hengyang 421001, Peoples R China.;[Fu, Yuchang] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA.;[Zha, Xiaohui] Univ Ottawa, Ottawa Hosp, Res Inst, Ottawa, ON K1H 8L6, Canada.
通讯机构：
[Tang, Chaoke] U;Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.
关键词：
Niemann–Pick type C1;oxLDL;ERK1/2;COX-2;PPARα;cholesterol
摘要：
The Niemann–Pick type C1 (NPC1) is located mainly in the membranes of the late endosome/lysosome and controls the intracellular cholesterol trafficking from the late endosome/lysosome to the plasma membrane. It has been reported that oxidized low-density lipoprotein (oxLDL) can up-regulate NPC1 expression. However, the detailed mechanisms are not fully understood. In this study, we investigated the effect of oxLDL stimulation on NPC1 expression in THP-1 macrophages. Our results showed that oxLDL up-regulated NPC1 expression at both mRNA and protein levels in a dose-dependent and time-dependent manner. In addition, oxLDL also induced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Treatment with oxLDL significantly increased cyclooxygenase-2 (COX-2) mRNA and protein expression in the macrophages, and these increases were suppressed by the ERK1/2 inhibitor PD98059 or ERK1/2 small interfering RNA (siRNA) treatment. OxLDL up-regulated the expression of peroxisome proliferator-activated receptor α (PPARα) at the mRNA and protein levels, which could be abolished by COX-2 siRNA or COX-2 inhibitor NS398 treatment in these macrophages. OxLDL dramatically elevated cellular cholesterol efflux, which was abrogated by inhibiting ERK1/2 and/or COX-2. In addition, oxLDL-induced NPC1 expression and cellular cholesterol efflux were reversed by PPARα siRNA or GW6471, an antagonist of PPARα. Taken together, these results provide the evidence that oxLDL can up-regulate the expression of the NPC1 through ERK1/2/COX-2/PPARα-signaling pathway in macrophages.
作者机构：
Institute of Cardiovascular Research,Key Laboratory for Atherosclerology of Hunan Province,Life Science Research Center,University of South China
摘要：
Reverse cholesterol transport (RCT) has been characterized as a crucial step for antiatherosclerosis, which is initiated by ATP-binding cassette A1 (ABCA1) to mediate the efflux of cellular phospholipids and cholesterol to lipid-free apolipoprotein A-I (apoA-I). However, the mechanisms underlying apoA-I/ABCA1 interaction to lead to the lipidation of apoA-I are poorly understood. There are several models proposed for the interaction of apoA-I with ABCA1 as well as the lipidation of apoA-I mediated by ABCA1. ApoA-I increases the levels of ABCA1 protein markedly. In turn, ABCA1 can stabilize apoA-I. The interaction of apoA-I with ABCA1 could activate signaling molecules that modulate posttranslational ABCA1 activity or lipid transport activity. The key signaling molecules in these processes include protein kinase A (PKA), protein kinase C (PKC), Janus kinase 2 (JAK2), Rho GTPases and Ca2+, and many factors also could influence the interaction of apoA-I with ABCA1. This review will summarize these mechanisms for the apoA-I interaction with ABCA1 as well as the signal transduction pathways involved in these processes.
摘要：
Atherosclerosis (As) is now widely appreciated to represent a chronic inflammatory reaction of the vascular wall in response to dyslipidemia and endothelial distress involving the inflammatory recruitment of leukocytes and the activation of resident vascular cells. MicroRNAs (miRNAs) are a group of endogenous, small (similar to 22 nucleotides in length) non-coding RNA molecules, which function specifically by base pairing with mRNA of genes, thereby induce translation repressions of the genes within metazoan cells. Recently, the function of miR-27, one of the miRNAs, in the initiation and progression of atherosclerosis has been identified. In vivo and in vitro studies suggest that miR-27 may serve as a diagnostic and prognostic marker for atherosclerosis. More recently, studies have identified important roles for miR-27 in angiogenesis, adipogenesis, inflammation, lipid metabolism, oxidative stress, insulin resistance and type 2 diabetes, etc. In this review, we focus on the role of miR-27 in the development of vulnerable atherosclerotic plaques, potential as a disease biomarker and novel therapeutic target in atherosclerosis. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE,2012年29(5):946-956 ISSN：1107-3756
通讯作者：
Tang, Chao-Ke
作者机构：
[Zhao, Guo-Jun; Lv, Yun-Cheng; Jiang, Zhi-Sheng; Tang, Chao-Ke; Yin, Kai; Ouyang, Xin-Ping; Jiang, Jin; Mo, Zhong-Cheng] Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Hunan, Peoples R China.;[Fu, Yuchang] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA.
通讯机构：
[Tang, Chao-Ke] U;Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Hunan, Peoples R China.
关键词：
atherosclerosis;epigallocatechi n-3-gallate;ATP-binding membrane cassette transporter A1;Nrf2/Keap1 pathway;nuclear factor-kappa B
摘要：
The ATP-binding membrane cassette transporter A1 (ABCA1) plays a protective role in the development of atherosclerosis for the reverse cholesterol transport process. Epigallocatechin-3-gallate (EGCG), which exists abundantly in green tea, exerts an anti-atherosclerotic effect via anti-inflammatory and metabolic regulation activities. Many genes and proteins related to lipid metabolism are involved in the lowering cholesterol effects of EGCG. However, effects of EGCG on ABCA1 have rarely been described. In the study presented here, we found that exposure of macrophage foam cells to TNF-α results in a downregulation of ABCA1 and a decrease in cholesterol efflux to apoA1, which is attenuated by pretreatment with EGCG. Moreover, rather than activating the Liver X receptor (LXR) pathway, inhibition of the TNF-α-induced nuclear factor-κB (NF-κB) activity is detected with EGCG treatment in cells. In order to inhibit the NF-κB activity, EGCG can promote the dissociation of the nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) complex; when the released Nrf2 translocates to the nucleus and activates the transcription of genes containing an ARE element inhibition of NF-κB occurs and Keap1 is separated from the complex to directly interact with IKKβ and thus represses NF-κB function. These results provide novel insight into the anti-inflammatory effects of EGCG, as well as the identification of a novel potential therapeutic role for the prevention of atherosclerosis.
作者机构：
[Shi-Lin Tang; Wu-Jun Chen; Kai Yin; Guo-Jun Zhao; Zhong-Cheng Mo; Yun-Cheng Lv; Xin-Ping Ouyang; Chao-Ke Tang] Institute of Cardiovascular Research,Key Laboratory for Atherosclerology of Hunan Province,Life Science Research Center,University of South China
会议名称：
第11届全国脂质与脂蛋白学术会议
会议时间：
2012-09-21
会议地点：
中国山西太原
会议论文集名称：
第11届全国脂质与脂蛋白学术会议论文汇编
摘要：
<正>Pregnancy-associated plasma protein-A（PAPP-A） has been involved in the atherosclerotic process through regulation of local expression of IGF-1 that mediates the activation of the phosphatidylinositol-3（PI3-K ） and Akt kinase（Akt ） signaling cascades which lead to constitutive nitric oxide formation,with its attending vasodilator,antiplatelet and insulin-sensitizing actions.In addition,IGF-1 may decreased cholesterol efflux through reductions of expression in ABCA1 and SR-B1 by the PI3-K/Akt signaling pathway.In the current study,we examined whether
作者：
Kai Yin;Zhi-Sheng Jiang;Chao-Ke Tang;Guang-hui Tu;Jing-Feng Li;...
作者机构：
[Kai Yin; Guang-hui Tu; Jing-Feng Li; Wu-Jun Chen; Guo-Jun Zhao; Xin-Ping YangOu; Yun-Cheng LV; Qian Lu; Yuchang Fu; Zhi-Sheng Jiang; Chao-Ke Tang] From Institute of Cardiovascular Research,Key Laboratory for Atherosclerology of Hunan Province,Life Science Research Center,University of South China;[Kai Yin; Guang-hui Tu; Jing-Feng Li; Wu-Jun Chen; Guo-Jun Zhao; Xin-Ping YangOu; Yun-Cheng LV; Qian Lu; Yuchang Fu; Zhi-Sheng Jiang; Chao-Ke Tang] Department of Diagnostics,The Medical College,University of South China;[Kai Yin; Guang-hui Tu; Jing-Feng Li; Wu-Jun Chen; Guo-Jun Zhao; Xin-Ping YangOu; Yun-Cheng LV; Qian Lu; Yuchang Fu; Zhi-Sheng Jiang; Chao-Ke Tang] Department of pathology,Nan Xian Peoples Hospital;[Kai Yin; Guang-hui Tu; Jing-Feng Li; Wu-Jun Chen; Guo-Jun Zhao; Xin-Ping YangOu; Yun-Cheng LV; Qian Lu; Yuchang Fu; Zhi-Sheng Jiang; Chao-Ke Tang] Department of Nutrition Sciences,University of Alabama at Birmingham,Birmingham,AL 35294-0012,USA
会议名称：
第11届全国脂质与脂蛋白学术会议
会议时间：
2012-09-21
会议地点：
太原
会议论文集名称：
第11届全国脂质与脂蛋白学术会议论文集
摘要：
<正>Aims:Apolipoprotein A-I(apoA-I),the major component of high-density lipoprotein(HDL),can suppress the lipopolysaccharide(LPS)-induced inflammatory response in macrophages.The role of apoA-1 in LPS-
摘要：
高密度脂蛋白(high density lipoprotein,HDL)是参与胆固醇逆向转运(即促进细胞内胆固醇流出,并转运到肝脏进行代谢)的关键脂蛋白,具有显著的抗动脉粥样硬化(atherosclerosis,AS)的作用[1].作为一种脂质与蛋白质的复合物,HDL除参与调节脂质代谢外,还具有抑制炎症[2]、氧化应激[3]和血栓形成[4]等作用.最新研究显示,HDL还具有调节糖代谢的作用,这为2型糖尿病(T2DM)和AS的防治提供了新的思路.
摘要：
Pregnancy-associated plasma protein-A (PAPP-A) has been involved in the atherosclerotic process through regulation of local expression of IGF-1 that mediates the activation of the phosphatidylinositol-3 (PI3-K) and Akt kinase (Akt) signaling cascades which lead to constitutive nitric oxide formation, with its attending vasodilator, antiplatelet and insulin-sensitizing actions. In addition, IGF-1 may decreased cholesterol efflux through reductions of expression in ABCA1 and SR-B1 by the PI3-K/Akt signaling pathway. In the current study, we examined whether PAPP-A was involved in LXRα regulation and in expression of ABCA1, ABCG1 or SR-B1 through the IGF-I-mediated signaling pathway (IGF/PI3-K/Akt). Results showed that PAPP-A significantly decreased expression of ABCA1, ABCG1 and SR-BI at both transcriptional and translational levels in a dose-dependent and time-dependent manner. Cellular cholesterol content was increased while cholesterol efflux was decreased by PAPP-A treatment. Moreover, LXRα which can regulate the expression of ABCA1, ABCG1 and SR-B1, was also down-regulated by PAPP-A treatment. LXRα-specific activation by LXRα agonist almost rescued the down-regulation of ABCA1, ABCG1 and SR-B1 expression by PAPP-A. In addition, PAPP-A can induce the IGF-1/PI3-K/Akt pathway in macrophages. Furthermore, our results indicate that the decreased levels observed in LXRα, ABCA1, ABCG1 and SR-B1 mRNA and protein levels upon treating cells with PAPP-A were strongly impaired with the PI3-K inhibitors or IGF-1R siRNA while the MAPK cascade inhibitor did not execute this effect, indicating that the process of ABCA1, ABCG1 and SR-BI degradation by PAPP-A involves the IGF-1/PI3-K/Akt pathway. In conclusion, PAPP-A may first down-regulate expression of LXRα through the IGF-1/PI3-K/Akt signaling pathway and then decrease expression of ABCA1, ABCG1, SR-B1 and cholesterol efflux in THP-1 macrophage-derived foam cells. Therefore, our study provided one of the mechanisms for understanding the critical effect of PAPP-A in pathogenesis of atherosclerosis.
