摘要:
MicroRNAs are a group of endogenous, small non-coding RNA molecules that can induce translation repression of target genes within metazoan cells by specific base pairing with the mRNA of target genes. Recently, microRNA-33 has been discovered as a key regulator in the initiation and progression of atherosclerosis. This review highlights the impact of microRNA-33-mediated regulation in the major cardiometabolic risk factors of atherosclerosis including lipid metabolism (HDL biogenesis and cholesterol homeostasis, fatty acid, phospholipid and triglyceride, bile acids metabolism), inflammatory response, insulin signaling and glucose/energy homeostasis, cell cycle progression and proliferation, and myeloid cell differentiation. Understanding the etiology and pathophysiology of microRNA-33 in atherosclerosis may provide basic knowledge for the development of novel therapeutic targets for ameliorating atherosclerosis and cardiovascular disease.
摘要:
To investigate the effects of neopterin on ABCA1 expression and cholesterol efflux in human THP-1 macrophage-derived foam cells, and to explore the role of the liver X receptor alpha (LXRα) involved. In the present study, THP-1 cells were pre-incubated with ox-LDL to become foam cells. The protein and mRNA expression were examined by Western blot assays and real-time quantitative PCR, respectively. Liquid scintillation counting and high performance liquid chromatography assays were used to test cellular cholesterol efflux and cholesterol content. Neopterin decreased ABCA1 expression and cholesterol efflux in a time- and concentration-dependent manner in THP-1 macrophage-derived foam cells, and the LXRα siRNA can reverse the inhibitory effects induced by neopterin. Neoterin has a negative regulation on ABCA1 expression via the LXRα signaling pathway, which suggests the aggravated effects of neopterin on atherosclerosis.
摘要:
Apelin has an antiatherogenic function through activating protein kinase C (PKC) to initiate a series of cellular signaling pathways. PKC phosphorylates and stabilizes ATP-binding cassette transporter A1 (ABCA1) through inhibiting its degradation mediated by calpain. Thus, in the present study, we investigated whether apelin-13 affects expression of ABCA1 through PKC signaling. The results showed that apelin-13 dramatically increased cholesterol efflux from THP-1 macrophage-derived foam cells and reduced cellular cholesterol levels. ABCA1 protein but not mRNA levels were dramatically increased by apelin-13, and calpain-induced degradation of ABCA1 and calpain activity were suppressed with treatment of apelin-13. However, the effects of apelin-13 on ABCA1 protein expression, cellular cholesterol efflux and calpain activity were abolished by depletion of PKCα, suggesting the potential important role of PKCα. In addition, apelin-13 was shown to phosphorylate serine residues in ABCA1 through the PKCα pathway. Thus, apelin-13 appears to activate PKCα, phosphorylate ABCA1 and inhibit calpain-mediated proteolysis, thereby promoting cholesterol efflux and reducing foam cell formation. Our study herein described a possible mechanism for understanding the antiatherogenic effects of apelin on attenuating the progression of atherosclerosis.
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.
摘要:
AIM: Apolipoprotein A-I (apoA-I), the major component of high-density lipoprotein (HDL), has been recently found to suppress inflammation. This study was to investigate the effects and potential mechanisms of apoA-I on the CD40/CD40 ligand (CD40L) proinflammatory signaling pathway. METHODS: Human THP-1 macrophage-derived foam cells were treated with sCD40L alone or in the presence of apoA-I. Secretion of proinflammatory cytokines was performed by enzyme-linked immunosorbent assay(ELISA). The proteins and mRNA expression were examined by western-blot and real-time PCR analysis, respectly. Cholesterol efflux was assessed by liquid scintillation counting. Cholesterol depletion of macrophages was performed with methylated beta-cyclodextrin. RESULTS: ApoA-I inhibits the inflammatory response stimulated by soluble CD40L (sCD40L) in macrophages. In addition, apoA-I inhibited the sCD40L-stimulated activation of nuclear factor-kB (NF-kB). The apoA-I-induced NF-kB deactivation was related to the decreased recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF-6), a crucial adapter protein for CD40 in macrophages, to lipid rafts after being treated by sCD40L. When interfering the expression of ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transporter for apoA-I in macrophages, it could significantly diminish the effect of apoA-I on the sCD40L-stimulated inflammatory response. CONCLUSION: ApoA-I suppresses CD40 proinflammatory signaling in macrophages by preventing TRAF-6 translocation to lipid rafts through ABCA1-dependent regulation of free cholesterol (FC) efflux, which may present a novel mechanism of apoA-I-mediated inflammation inhibition in macrophages.
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.
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.
摘要:
Background Macrophage migration inhibitory factor (MIF) is an upstream regulator in immune and inflammatory responses. However, its role in viral myocarditis remains unknown. In this study, we investigated the role of the MIF in coxsackievirus B3 (CVB3)-induced myocarditis. Methods Mice were randomized into two groups receiving either Eagle’s minimal essential medium (EMEM, control group) or virus solution (infected group). Subsets of mice in the infected group were sacrificed on days 3, 7, 14 and 28 after inoculation. Expression of MIF was detected using an enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction and immunohistochemistry. A neutralizing antibody (Ab) to MIF was injected intraperitoneally from day 0 to 7 after inoculation. Disease severity was estimated by histopathology of the heart and by the heart weight to body weight ratio, and the interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) in the myocardium were measured by ELISA on day 14. Results The serum MIF concentration and expression levels of myocardial MIF mRNA and protein were significantly elevated in mice on days 7 and 14 post-infection. The survival rate was markedly higher and disease severity was obviously less in mice treated with anti-MIF Ab. Furthermore, MIF blockade significantly decreased the IL-1β and TNF-α in the myocarditic heart. Conclusion These results demonstrate that MIF is an important naturally occurring inflammatory cytokine in CVB3-induced myocarditis, and anti-MIF Ab may lessen the inflammatory response.
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.
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.
作者机构:
[Zhou, Shouhong; Tian, Shaowen; Ouyang, Xinping; Qiao, Ge; Wang, Ling] Univ S China, Coll Med, Dept Physiol, Hengyang 421001, Hunan, Peoples R China.;[Li, Peng] Univ S China, Coll Life Sci & Technol, Dept Biol, Hengyang 421001, Hunan, Peoples R China.;[Tang, Chaoke; Ouyang, Xinping] Univ S China, Life Sci Res Ctr, Inst Cardiovasc Dis, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Tian, Shaowen] U;Univ S China, Coll Med, Dept Physiol, Hengyang 421001, Hunan, Peoples R China.
关键词:
Behavioral sensitization;Memory;Morphine;Rapid eye movement sleep deprivation;Sleep
摘要:
Previous studies have shown that behavioral sensitization is modulated by drug-associated context, in which memory processes may be critically involved. Sleep has been suggested to play an important role in memory processes. However, the relationship between sleep and context-modulated effects on behavioral sensitization remains to be elucidated. In the present study, we designed three experiments to explore the effects of rapid eye movement sleep deprivation (RSD) on context-modulated effects on morphine locomotor sensitization in mice. Mice were subjected to 6 h RSD starting either immediately after morphine pairing training or 6 h later. The control mice were returned to their home cages immediately after pairing training and left undisturbed. In experiment 1, RSD from 0 to 6h but not from 7 to 12 h disrupted paired context-modulated enhancement of locomotor activity. In experiment 2, RSD from 0 to 6 h but not from 7 to 12 h disrupted unpaired context-modulated suppression of locomotor activity. In experiment 3, RSD from either 0 to 6h or 7 to 12 h had no effect on conditioned locomotor activity. Our findings suggest that sleep plays a critical role in memory processes underlying context-modulated effects on morphine locomotor sensitization. (C) 2011 Elsevier Ireland Ltd. All rights reserved.