摘要：
The aryl hydrocarbon receptor (AhR) is a period-aryl hydrocarbon receptor nuclear transporter-simple minded domain transcription factor that shares structural similarity with circadian clock genes and readily interacts with components of the molecular clock. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters behavioral circadian rhythms and represses the Period1 (Per1) gene in murine hematopoietic stem and progenitor cells. Per1 expression is driven by circadian locomotor activity cycles kaput-brain muscle ARNT-like (CLOCK-BMAL1)–dependent activation of Eboxes in the Per1 promoter. We hypothesized that the effects of AhR activation on the circadian clock are mediated by disruption of CLOCK-BMAL1 function and subsequent Per1 gene suppression. Effects of AhR activation on rhythmic Per1 transcripts were examined in livers of mice after treatment with the AhR agonist, TCDD; the molecular mechanisms of Per1 repression by AhR were determined in hepatoma cells using TCDD and β-napthoflavone as AhR activators. This study reports, for the first time, that AhR activation by TCDD alters the Per1 rhythm in the mouse liver and that Per1 gene suppression depends upon the presence of AhR. Furthermore, AhR interaction with BMAL1 attenuates CLOCK-BMAL1 activity and decreases CLOCK binding at Ebox1 and Ebox3 in the Per1 promoter. Taken together, these data suggest that AhR activation represses Per1 through disrupting CLOCK-BMAL1 activity, producing dysregulation of rhythmic Per1 gene expression. These data define alteration of the Per1 rhythm as novel signaling events downstream of AhR activation. Downregulation of Per1 could contribute to metabolic disease, cancer, and other detrimental effects resulting from exposure to certain environmental pollutants.
摘要：
Atherosclerosis is characterized by a chronic inflammatory condition that involves numerous cellular and molecular inflammatory components. A wide array of inflammatory mediators, such as cytokines and proteins produced by macrophages and other cells, play a critical role in the development and progression of the disease. ATP-binding membrane cassette transporter A1 (ABCA1) is crucial for cellular cholesterol efflux and reverse cholesterol transport (RCT) and is also identified as an important target in antiatherosclerosis treatment. Evidence from several recent studies indicates that inflammation, along with other atherogenic-related mediators, plays distinct regulating roles in ABCA1 expression. Proatherogenic cytokines such as interferon (IFN)-γ and interleukin (IL)-1β have been shown to inhibit the expression of ABCA1, while antiatherogenic cytokines, including IL-10 and transforming growth factor (TGF)-β1, have been shown to promote the expression of ABCA1. Moreover, some cytokines such as tumor necrosis factor (TNF)-α seem to regulate ABCA1 expression in species-specific and dose-dependent manners. Inflammatory proteins such as C-reactive protein (CRP) and cyclooxygenase (COX)-2 are likely to inhibit ABCA1 expression during inflammation, and inflammation induced by lipopolysaccharide (LPS) was also found to block the expression of ABCA1. Interestingly, recent experiments revealed ABCA1 can function as an antiinflammatory receptor to suppress the expression of inflammatory factors, suggesting that ABCA1 may be the molecular basis for the interaction between inflammation and RCT. This review aims to summarize recent findings on the role of inflammatory cytokines, inflammatory proteins, inflammatory lipids, and the endotoxin-mediated inflammatory process in expression of ABCA1. Also covered is the current understanding of the function of ABCA1 in modulating the immune response and inflammation through its direct and indirect antiinflammatory mechanisms including lipid transport, high-density lipoprotein (HDL) formation and apoptosis.
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.
作者：
He Qing-Zhi;Tuo Qin-Hui;Zeng Huai-Cai;Zhu Bing-Yang;Rang Wei-Qing;...
期刊：
生物化学与生物物理进展,2010年37(8):881-890 ISSN：1000-3282
通讯作者：
Tang Xiao-Qing
作者机构：
[Zhu Bing-Yang; Tuo Qin-Hui; Liao Duan-Fang; He Qing-Zhi] Univ S China, Prov Key Lab Pharmacoprotom, Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.;[Tang Xiao-Qing] Univ S China, Dept Physiol, Sch Med, Hengyang 421001, Peoples R China.;[Liao Duan-Fang] Hunan Univ Chinese Med, Dept Tradit Chinese Diagnot, Sch Pharm, Changsha 410208, Hunan, Peoples R China.;[Rang Wei-Qing; Zeng Huai-Cai] Univ S China, Sch Publ Hlth, Hengyang 421001, Peoples R China.
通讯机构：
[Tang Xiao-Qing] U;Univ S China, Dept Physiol, Sch Med, Hengyang 421001, Peoples R China.
关键词：
Daxx;Ox-LDL;macrophage;apoptosis;caveolin-1
摘要：
To explore whether Daxx mediates oxidized low-density lipoprotein (Ox-LDL)-induced cholesterol accumulation and apopotosis in macrophage and the underlying molecular mechanisms, intracellular lipid droplets and lipid levels were assayed by oil red O staining and high performance liquid chromatography (HPLC), respectively, the apoptotic effect of RAW264.7 cells induced by Ox-LDL was analyzed by flow cytometric analysis and acridine orange/ethidium bromide (AO/EB) staining, the mRNA expressions of Daxx was quantified by Real time RT- PCR, the protein expression of caveolin-1 was detected by Western-blotting, Daxx-specific small interfering RNA(Daxx siRNA) was transfected to RAW264.7 cell by lipofectamin. Ox-LDL up-regulated the expression of Daxx mRNA, increased the accumulation of intercellular cholesterol in RAW264.7 macrophages, and induced the apoptosis of RAW264.7 macrophages. However, Ox-LDL-induced intercellular cholesterol accumulation and apoptosis in RAW264.7 cells was prevented by Daxx siRNA. Ox-LDL also induced caveolin-1 expression and this effect is significantly suppressed by Daxx siRNA. It can be concluded that Daxx mediates Ox-LDL-induced cholesterol accumulation and apoptosis in macrophages by up-regulating caveolin-1 expression. These findings provide an important demonstration that Daxx might be associated with the development of atherosclerosis.
摘要：
Cholesterol efflux from lipid-loaded cells is a key athero-protective event that counteracts cholesterol uptake. The imbalance between cholesterol efflux and uptake determines the prevention or development of atherosclerosis. Many proteins and factors participate in the cholesterol efflux event. However, there are currently no systematic models of reverse cholesterol transport (RCT) that include most RCT-related factors and events. On the basis of recent research findings from other and our laboratories, we propose a novel model of one center and four systems with coupling transportation and networking regulation. This model represents a common way of cholesterol efflux; however, the systems in the model consist of different proteins/factors in different cells. In this review, we evaluate the novel model in vascular smooth muscle cells (VSMCs) and macrophages, which are the most important original cells of foam cells. This novel model consists of 1) a caveolae transport center, 2) an intracellular trafficking system of the caveolin-1 complex, 3) a transmembrane transport system of the ABC-A1 complex, 4) a transmembrane transport system of the SR-B1 complex, and 5) an extracelluar trafficking system of HDL/Apo-A1. In brief, the caveolin-1 system transports cholesterol from intracellular compartments to caveolae. Subsequently, both ABC-A1 and SR-B1 complex systems transfer cholesterol from caveolae to extracellular HDL/Apo-A1. The four systems are linked by a regulatory network. This model provides a simple and concise way to understand the dynamic process of atherosclerosis.
作者机构：
[Zhu Bing-Yang; Luo Di-Xian; Xu Can-Xin; Wang Chun; Gao Zhi-Ping; Liao Duan-Fang] Univ S China, Life Sci Res Ctr, Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.;[Liao Duan-Fang] Hunan Univ Chinese Med, Dept Tradit Chinese Diagnost, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Liao Duan-Fang] U;Univ S China, Life Sci Res Ctr, Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.
摘要：
Apelin is the endogenous ligand of the G protein-coupled receptor, APJ. Vascular smooth muscle cells express both apelin and APJ, which are important regulatory factors in the cardiovascular and nervous systems. Importantly, APJ is also involved in the pathogenesis if HIV-1 infection. We investigated whether vascular smooth muscle cell proliferation was regulated through an apelin-pERK1/2-cyclin D1 signal transduction pathway. Apelin-13 significantly stimulated vascular smooth muscle cell proliferation and increased cell cycle progression. Apelin-13 a decreased the proportion of cell in the G0/G1 phase while increasing the number of cells in S phase. Apelin-13 also increased the levels of cyclin D1, cyclin E and pERK1/2. Treatment of cells with the MEK inhibitor PD98059 attenuated the apelin-3-induced pERK1/2 activation. Similarly, treatment with PD98059 partially diminished the apelin-13-induced expression of cyclin D1 and vascular smooth muscle cell proliferation. Taken together, these data established that apelin-13 stimulates vascular smooth muscle cell proliferation by promoting the G1-S phase transition, and that this effect is mediated in part by an apelin-pERK1/2-cyclin D1 signal cascade.
作者机构：
[杨云波] Department of Pharmacology, Institute of Pharmacy, Traditional Chinese Medical College, Changsha 410007, China;Inst. of Pharmacy and Pharmacology, Nanhua University, Hengyang 421001, China;[黄红林; 廖端芳; 谢志忠] Department of Pharmacology, Institute of Pharmacy, Traditional Chinese Medical College, Changsha 410007, China, Inst. of Pharmacy and Pharmacology, Nanhua University, Hengyang 421001, China
通讯机构：
[Yang, Y.-B.] D;Department of Pharmacology, Institute of Pharmacy, Traditional Chinese Medical College, China
