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
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
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.
期刊：
Journal of Atherosclerosis and Thrombosis,2011年18(9):796-807 ISSN：1340-3478
通讯作者：
Tang, Chao-Ke
作者机构：
[Tang, Chao-Ke; Li, Xiao-Xu; Hu, Yan-Wei; Liu, Xie-Hong; Tang, Ya-Ling; Mo, Zhong-Cheng; Yi, Guang-Hui; Wang, Zuo; Xiao, Ji] Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.;[Liao, Duan-Fang] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha, Hunan, Peoples R China.
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, Peoples R China.
关键词：
Advanced oxidation protein products;ATP-binding cassette transporter A1;JAK/STAT;Cholesterol efflux
摘要：
AIMS: Advanced oxidation protein products (AOPPs) are new independent risk factor for coronary artery disease. This study was to determine the effects and potential mechanisms of AOPPs on cholesterol efflux from human macrophage foam cells. METHODS: Human THP-1 monocytes were preincubated with Phorbol-12-myristate- 13-acetate (PMA) and oxidized low density lipoprotein (ox-LDL) to form foam cells. The protein and mRNA expression were examined by western immunoblotting assays and real-time quantitative PCR, respectively. Cellular cholesterol content was measured by HPLC. The cholesterol efflux was assessed by liquid scintillation counting. RESULTS: AOPPs significantly decreased the expression of ATP-binding membrane cassette transporter A-1 (ABCA1) and liver X receptor alpha (LXRalpha) and reduced cholesterol efflux from THP-1 macrophage- derived foam cells. AOPPs substantially activated NADPH oxidase and activated Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal pathway in THP-1-derived foam-like cells. Inhibiting NADPH oxidase by diphenyliodonium (DPI) effectively abolished the AOPPs-induced decrease in cholesterol efflux and the expression of ABCA1. Inhibiting JAK/STAT activation by its specific inhibitor AG-490 or by siRNA could also block AOPPs action on THP-1 cells. CONCLUSIONS: AOPPs may first down-regulate the expression of LXRalpha and ABCA1 through JAK/STAT signal pathway activation and then inhibit cholesterol efflux in THP-1-derived foam-like cells; therefore, our study may be useful for understanding the critical effects of AOPPs on the pathogenesis of atherosclerosis.
期刊：
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY,2010年56(3):309-319 ISSN：0160-2446
通讯作者：
Tang, Chao-Ke
作者机构：
[Tan, Chun-Zhi; Tang, Chao-Ke; Liu, Xie-Hong; Yin, Kai; Tang, Ya-Ling; Mo, Zhong-Cheng; Jiang, Jin; Xiao, Ji; Cui, Li-Bao] Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Changsha, Hunan, Peoples R China.;[Liu, Xie-Hong] Changsha Med Univ, Changsha, Hunan, Peoples R China.;[Liao, Duan-Fang] Hunan Univ Chinese Med, Changsha, Hunan, Peoples R China.;[Tang, Chao-Ke] Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.
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, Peoples R China.
关键词：
ABCA1, D4-F, Cdc42/cAMP/PKA, atherosclerosis, reverse cholesterol transport
摘要：
Adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays a crucial role in apolipoprotein A-I (apoA-I) binding activity and promotes cellular cholesterol efflux. ApoA-I mimetic peptide D4-F has reported to have the similar ability as apoA-I. However, the detailed mechanisms of ABCA1 regulation by D4-F are not understood. In the present study, we investigated the effects of D4-F on ABCA1 expression and ABCA1-dependent cholesterol efflux and examined the role of Cdc42/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway on the regulation of ABCA1 by D4-F in THP-1 macrophage-derived foam cells. Results showed that D4-F stabilized ABCA1 protein and enhanced ABCA1-dependent cholesterol efflux but had no effect on ABCA1 messenger RNA expression. We also revealed that D4-F enhanced cAMP level and PKA activity and ABCA1 serine phosphorylation. Short interfering RNA of PKA led to reduction of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux compensated by D4-F. PKA-specific activation by PKA agonist enhanced the upregulation of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux by D4-F. However, ABCA1 expression did not change by treatment with PKA agonist or PKA-short interfering RNA. We found that secramine B of Cdc42 inhibitor reduced the cAMP level compensated by D4-F. These results provide evidence that D4-F enhances ABCA1 serine phosphorylation and ABCA1-dependent cholesterol efflux through Cdc42/cAMP/PKA pathway in THP-1 macrophage-derived foam cells.
