Macrophage-derived Foam Cell Formation Research Articles

Nucleolin protects macrophages from oxLDL-induced foam cell formation through up-regulating ABCA1 expression

Our recent studies have indicated that nucleolin, as a multifunctional RNA-binding protein, exerts protective effects in the myocardial cells and endothelial cells under the condition of oxidative stress. However, the function of nucleolin and its potential mechanism in macrophage-derived foam cell formation remain largely unexplored. ApoE−/− mice were fed with a high-fat diet (HFD) for 10–24 weeks. Protein expression was measured by western blotting or immunofluorescence, and gene expression at the mRNA level was detected by qRT-PCR. The level of lipid in macrophages was examined by Oil Red O staining, high-performance liquid chromatography (HPLC) and NBD-cholesterol. Actinomycin D (Act D) was used to determine the stability of ABCA1 mRNA in macrophages. The interaction of nucleolin with ABCA1 mRNA was assessed using co-immunoprecipitation (co-IP). The aortas advanced plaques demonstrated significantly lower levels of nucleolin protein compared with early plaques in ApoE−/− mice, in which the macrophage foam cells occupied main body. Nucleolin expression at the mRNA and protein levels in RAW264.7 macrophages was significantly reduced by oxidized low-density lipoprotein (oxLDL) in a dose- and time-dependent manner. Furthermore, nucleolin overexpression markedly attenuated lipid accumulation in oxLDL-challenged macrophages through increasing cholesterol efflux. In addition, nucleolin overexpression significantly increased the expression of ATP-binding cassette transporter A1 (ABCA1) at the mRNA and protein levels without affecting expressions of scavenger receptors (SR)-A, SR-B1, CD36 and ATP-binding cassette transporter G1 (ABCG1) at the mRNA level. Moreover, nucleolin overexpression increased the stability of ABCA1 mRNA in macrophages, whereas nucleolin ablation abrogated the oxLDL-induced up-regulation of ABCA1. The up-regulation of ABCA1 by nucleolin resulted from its protein-RNA interaction. Our data suggested that nucleolin inhibited foam cell formation through enhancing stability of ABCA1 mRNA and subsequently increasing cholesterol efflux.

HOMOCYSTEINE ACCELERATED THE DISORDER OF LIPID METABOLISM VIA REGULATING PCSK9 AND LXRA-ABCA1/ABCG1 PATHWAY

Background: Homocysteine is an independent risk factor of atheroslceorsis, characterized by the formation of macrophage-derived foam cells. Liver X receptor alpha (LXRα) can keep cholesterol homeostasis, while proprotein convertase subtilisin/kexin 9(PCSK9), a lipid metabolism regulatory protein

Transcriptomic Analysis of THP‐1 Macrophages Exposed to Lipoprotein Hydrolysis Products Generated by Lipoprotein Lipase

Macrophage lipoprotein lipase (LPL) induces lipid accumulation and promotes atherosclerosis. However, the effects of lipoprotein hydrolysis products generated by LPL on macrophage-derived foam cell formation are not clearly understood. Thus, we analyzed the transcriptomic response to hydrolysis products via microarray analyses on RNA isolated from human THP-1 macrophages incubated with total lipoprotein hydrolysis products generated by LPL. The expression of 183 transcripts was significantly upregulated and 133 transcripts were significantly downregulated. Bioinformatics analyses revealed that there was a significant over-representation of genes involved in cell cycling, stress response, type I interferon signaling, cellular metal ion homeostasis, sterol metabolism, and nuclease activity. Interestingly, transcripts for 63 small nucleolar RNA were significantly upregulated. We verified the microarray data by quantitative real-time PCR and found that the expression of SNORA56, as well as the expression of genes associated with the cell cycle (PCNA and DKC1 variant 3), stress response (ATF3), type I interferon signaling (IFITM1), and lipid metabolism (CD36 and PLIN2) were significantly affected by LPL hydrolysis products. To determine if the free fatty acid (FFA) component of total lipoprotein hydrolysis products is sufficient to alter the expression of these genes, THP-1 macrophages were also incubated with the total FFA or individual classes of the FFA component. The gene regulation by the FFA component did not mimic that of the hydrolysis products, suggesting that the regulation of gene expression in THP-1 macrophages depends on the specific combination and concentration of lipid species present in the hydrolysis products, and not solely on FFA.

Retinol-Binding Protein-Dependent Cholesterol Uptake Regulates Macrophage Foam Cell Formation and Promotes Atherosclerosis.

Retinol-binding protein 4 (RBP4) is an adipokine that plays decisive roles in glucose metabolism and insulin sensitivity. Elevated circulating RBP4 levels were reported to be associated with increased risk for cardiovascular disease, but the precise role of RBP4 in atherosclerotic diseases and its mechanisms of action remain elusive. Serum RBP4 levels of 1683 participants from South China were evaluated and the occurrence of major adverse cardiovascular events was followed up for 5 years. Apolipoprotein E-deficient mice infected with RBP4-overexpressing/silencing adenovirus, J774A.1 macrophages, and primary peritoneal macrophages from RBP4 transgenic mice were used for investigating the function of RBP4 in foam cell formation. Prospective cohort studies revealed that baseline serum RBP4 level was an independent predictor for incidence of adverse cardiovascular events after adjustment for traditional risk factors. Increased RBP4 expression was observed in atherosclerotic lesions of aortic specimens from both humans and apolipoprotein E-deficient mice, and RBP4 was localized to areas rich in macrophage foam cells. RBP4 inhibition attenuated whereas overexpression accelerated atherosclerosis progression in apolipoprotein E-deficient mice. Both treatment with exogenous recombinant RBP4 and overexpression of RBP4 gene promoted macrophage-derived foam cell formation through the activation of scavenger-receptor CD36-mediated cholesterol uptake, and RBP4 transcriptionally upregulated CD36 expression in a manner dependent on jun N-terminal kinase and signal transducer and activator of transcription 1. The tyrosine kinase c-Src was identified as the upstream regulator of jun N-terminal kinase-signal transducer and activator of transcription 1-mediated CD36-dependent cholesterol uptake, and RBP4 challenge was found to alter the membrane distribution of c-Src and cause c-Src to partition into lipid-raft membrane subdomains, where the kinase was activated. Lastly, Toll-like receptor 4, but not retinol or stimulated by retinoic acid 6, mediated the inductive effects of RBP4 in macrophages. Inclusion of RBP4 levels in traditional models enhances the predictive ability for the incidence of atherosclerotic events. RBP4 promotes atherogenesis by inducing macrophage-derived foam cell formation.

Multifunctional Dextran Sulfate-Coated Reconstituted High Density Lipoproteins Target Macrophages and Promote Beneficial Antiatherosclerotic Mechanisms.

An atorvastatin calcium (AT)-loaded dextran sulfate (DXS)-coated core-shell reconstituted high density lipoprotein (rHDL), termed AT-DXS-LP-rHDL, was developed for targeted drug delivery to macrophages and suppression of inflammation via the high affinity of DXS with scavenge receptor class AI (SR-AI) as well as depletion of intracellular cholesterol by apolipoprotein A-I (apoA-I)-mediated cholesterol efflux. These core-shell nanoparticles comprising an AT-loaded negatively charged poly(lactide-co-glycolide) (PLGA) core and a cationic lipid bilayer shell were prepared by nanoprecipitation method followed by thin film hydration and extrusion. The nanoparticles were further functionalized with apoA-I and DXS via sodium cholate mediation and electrostatic interaction, respectively. The core-shell structure and the surface coating of apoA-I and DXS were verified by the increased particle size, inverted zeta potential, and reduced in vitro drug release rate. The TEM image further confirmed the entrapment of the PLGA nanoparticles in the aqueous interior of the liposomes. In vitro cell viability assay showed the biocompatibility of the AT-loaded nanocarriers. The cellular uptake study illustrated that the targeting efficacy to macrophages increased in the following order: PLGA nanoparticles (P-NP), core-shell nanoparticles (LP-NP), core-shell rHDL (LP-rHDL), and DXS-LP-rHDL. Moreover, cellular drug efficacy of AT-loaded nanoparticles in preventing macrophage-derived foam cell formation and inflammation such as intracellular lipid deposition, cholesterol esters content, DiI-oxLDL uptake, cholesterol efflux, and secretion of TNF-α, IL-6, and IL-10 was much better than that of the drug-free nanoparticles, consistent with the results of cellular uptake study. Collectively, AT-DXS-LP-rHDL, as multifunctional carriers, could not only deliver more drug to macrophages, but also present antiatherogenic actions of the biofunctional nanocarriers through damping oxidized low density lipoproteins (oxLDL) uptake and promoting cholesterol efflux.

Overexpressed PLTP in macrophage may promote cholesterol accumulation by prolonged endoplasmic reticulum stress

It is well known that phospholipid transfer protein (PLTP) is involved in the lipid metabolism and development of atherosclerosis (AS). Abundant PLTP is considered to be expressed on the foam cells derived from monocyte/macrophages in atherosclerotic plaques, suggesting that high level of active PLTP may promote the formation of foam cells. However, the exact role of PLTP on the process of macrophage derived foam cell formation remains unclear. The accumulation of free cholesterol (FC) in the cytoplasm may lead to the prolonged endoplasmic reticulum stress (ERs) and the imbalance of intracellular cholesterol homeostasis. Different PLTP level definitely alternates the phospholipids (PL) and cholesterol level in plasma, strongly suggesting that active PLTP may change the level of FC and PL intracellularly, which subsequently induced the ERs in macrophage. Thus, we hypothesize that high level of PLTP may promote the accumulation of cholesterol in macrophage via the alteration ratio of FC to PL. Therefore, validating this hypothesis may clarify the role of PLTP in macrophage ERs in AS and also raise a novel strategy in the regression of AS plaques via restoring intracellular membrane lipid homeostasis and attenuating ERs.

Gly[14]-humanin inhibits ox-LDL uptake and stimulates cholesterol efflux in macrophage-derived foam cells

Foam cell formation, which is caused by imbalanced cholesterol influx and efflux by macrophages, plays a vital role in the occurrence and development of atherosclerosis. Humanin (HN), a mitochondria-derived peptide, can prevent the production of reactive oxygen species and death of human aortic endothelial cells exposed to oxidized low-density lipoprotein (ox-LDL) and has a protective effect on patients with in early atherosclerosis. However, the effects of HN on the regulation of cholesterol metabolism in RAW 264.7 macrophages are still unknown. This study was designed to investigate the role of [Gly14]-humanin (HNG) in lipid uptake and cholesterol efflux in RAW 264.7 macrophages. Flow cytometry and live cell imaging results showed that HNG reduced Dil-ox-LDL accumulation in the RAW 264.7 macrophages. A similar result was obtained for lipid accumulation by measuring cellular cholesterol content. Western blot analysis showed that ox-LDL treatment upregulated not only the protein expression of CD36 and LOX-1, which mediate ox-LDL endocytosis, but also ATP-binding cassette (ABC) transporter A1 and ABCG1, which mediate ox-LDL exflux. HNG pretreatment inhibited the upregulation of CD36 and LOX-1 levels, prompting the upregulation of ABCA1 and ABCG1 levels induced by ox-LDL. Therefore we concluded that HNG could inhibit ox-LDL-induced macrophage-derived foam cell formation, which occurs because of a decrease in lipid uptake and an increase in cholesterol efflux from macrophage cells.

Endophilin-A2-mediated increase in scavenger receptor expression contributes to macrophage-derived foam cell formation

Background and aimsMacrophage-derived foam cell formation (MFCF) is a crucial step in the pathogenesis of atherosclerosis. Uptake of oxidized low-density lipoprotein (oxLDL) by scavenger receptors is indispensable for MFCF. Endophilin-A2 has been reported to regulate clathrin-mediated endocytosis (CME). In this study, we tested the hypothesis that endophilin-A2 regulates oxLDL uptake and MFCF by mediating CME of oxLDL-scavenger receptor complexes. MethodsIn vitro MFCF was induced by oxLDL treatment. Involvement of endophilin-A2 in oxLDL cytomembrane binding, cellular uptake, and MFCF was evaluated by manipulation of endophilin-A2. ResultsEndophilin-A2 was involved in MFCF via scavenger receptor CD36 and scavenger receptor-A (SR-A)-mediated positive feedback pathways. We observed that oxLDL triggered interaction of endophilin-A2 with CD36 or SR-A, and induced an endophilin-A2-dependent activation of the apoptosis signal-regulating kinase-1 (ASK1)/Jun N-terminal kinase (JNK)/p38 signaling pathway. The activation of ASK1-JNK/p38 signal increased expression of both CD36 and SR-A, which promoted oxLDL cytomembrane binding, cellular uptake, and MFCF. In the absence of oxLDL, endophilin-A2 up-regulated the expression of receptors and Dil-oxLDL binding and uptake, but not the intracellular accumulation of lipids. In the presence of oxLDL, the CME inhibitors pitstop2 and ikarugamycin mimicked the inhibiting effect of endophilin-A2 knockdown and eliminated the elevating effect of endophilin-A2 overexpression on oxLDL uptake and MFCF. ConclusionsEndophilin-A2 was identified as a novel molecule regulating MFCF by mechanisms attributable to CME and beyond CME.

Autophagy is associated with cell fate in the process of macrophage-derived foam cells formation and progress.

BackgroundAutophagy participates in plaque formation and progression; however, its association with foam cells’ fate is unknown. To investigate autophagy features and its effect on the fate of different-stage macrophage foam cells (FCs). Different-stage FCs were obtained through incubation of THP-1 macrophages (THP-M) with oxidized low-density lipoprotein LDL (oxLDL, 80 μg/mL) for various durations (0–72 h). Autophagy in THP-1 macrophage FCs and in apoE−/− mice was regulated by Rapamycin (80 ug/mL) or 3-MA (10 mM). Lipid droplet accumulation, LC3 I/II, P62 expression level, and autophagic flux were measured. Vascular ultrasound, TUNEL, IHC, and DHE staining were used to detect the artery plaques in apoE−/− mice.ResultsIn early-stage FCs, the amount of autophagosomes gradually increased, and autophagic flux intensity accelerated, but in mid-late stage FCs, autophagic flux was suppressed. For early stage FCs, treatment with autophagy activator rapamycin markedly decreased intracellular lipid content and prevented them from transforming into foam cells, while the autophagy inhibitor 3-MA considerably increased the intracellular lipid-droplet accumulation. During the process of foam cell development, upregulating autophagy not only reduced intracellular lipid-droplet accumulation, but also inhibited cell apoptosis through clearing dysfunctional mitochondria and lowering intracellular ROS level. The in vivo experiments produced consistent results that rapamycin administration in apoE−/− mice reduced the death rate of macrophages and delayed plaque progression.ConclusionsThe fate of macrophage FCs was associated with autophagy. Early autophagy enhancement inhibits the formation and progression of macrophage FCs and prevents atherosclerosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0274-z) contains supplementary material, which is available to authorized users.

Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis.

ATP-binding cassette transporter A1 (ABCA1) plays a critical role in maintaining cellular cholesterol homeostasis. The purpose of this study is to identify the molecular mechanism(s) underlying ABCA1 epigenetic modification and determine its potential impact on ABCA1 expression in macrophage-derived foam cell formation and atherosclerosis development. DNA methylation induced foam cell formation from macrophages and promoted atherosclerosis in apolipoprotein E-deficient (apoE−/−) mice. Bioinformatics analyses revealed a large CpG island (CGI) located in the promoter region of ABCA1. Histone methyltransferase enhancer of zeste homolog 2 (EZH2) downregulated ABCA1 mRNA and protein expression in THP-1 and RAW264.7 macrophage-derived foam cells. Pharmacological inhibition of DNA methyltransferase 1 (DNMT1) with 5-Aza-dC or knockdown of DNMT1 prevented the downregulation of macrophage ABCA1 expression, suggesting a role of DNA methylation in ABCA1 expression. Polycomb protein EZH2 induced DNMT1 expression and methyl-CpG-binding protein-2 (MeCP2) recruitment, and stimulated the binding of DNMT1 and MeCP2 to ABCA1 promoter, thereby promoting ABCA1 gene DNA methylation and atherosclerosis. Knockdown of DNMT1 inhibited EZH2-induced downregulation of ABCA1 in macrophages. Conversely, EZH2 overexpression stimulated DNMT1-induced ABCA1 gene promoter methylation and atherosclerosis. EZH2-induced downregulation of ABCA1 gene expression promotes foam cell formation and the development of atherosclerosis by DNA methylation of ABCA1 gene promoter.

Porphyromonas gingivalis infected macrophages upregulate CD36 expression via ERK/NF-κB pathway

CD36, a scavenger receptor, plays an important role in the progression of atherosclerosis through its interaction with oxidized low-density lipoprotein (ox-LDL). Porphyromonas gingivalis (P. gingivalis, Pg) has been shown to promote macrophage-derived foam cell formation by affecting the expression of CD36. However, the regulatory role of CD36 in macrophages infected with Pg remains largely unknown. Therefore, the aim of the present study was to explore the molecular mechanism of Pg induced CD36 expression in macrophages. Our results showed that Pg promoted ox-LDL uptake by macrophages and the formation of foam cells. Pg infection increased CD36 mRNA and protein levels in ox-LDL-untreated macrophages. Moreover, small interferon RNA (siRNA) targeting CD36 significantly reduced foam cell formation induced by Pg. Additionally, Pg stimulated nuclear translocation of p65, which directly bound to the promoters of CD36 to facilitate its transcription. Inhibition of p65, NF-κB or ERK1/2 blocked Pg-induced CD36 production; whereas, overexpression of NF-κB subunits p65 and p50 upregulated CD36. Furthermore, Ras inhibitors significantly attenuated ERK1/2 activation and CD36 expression. Taken together, the data indicated that stimulation of the ERK/NF-κB pathway by Pg led to transactivation of the CD36 promoters, thereby upregulating CD36 expression in the infected macrophages. These findings may help design new treatment strategies in atherosclerosis.

Luteolin Attenuates Foam Cell Formation and Apoptosis in Ox-LDL-Stimulated Macrophages by Enhancing Autophagy

Background: Our previous studies demonstrated that luteolin, which is rich in flavones, has various biological properties and can exert anti-oxidant, anti-inflammatory and anti-apoptotic activities. However, its effect on ox-LDL-induced macrophage lipid accumulation and apoptosis has not been revealed. Aims: This study aimed to explore the role of luteolin in ox-LDL-induced macrophage-derived foam cell formation and apoptosis and to delineate the underlying mechanism. Methods: Murine RAW264.7 cells were stimulated with oxidized low-density lipoprotein (ox-LDL) (50 µg/ml) for 24 h and then pretreated with 25 µM luteolin for another 24 h. The effects of luteolin on lipid accumulation in RAW264.7 cells induced by ox-LDL were assayed using Oil red O staining and high performance liquid chromatography (HPLC). Apoptosis was confirmed by acridine orange/ethidium bromide (AO/EB) staining, flow cytometric analysis and the TUNEL assay. Immunofluorescence, Western blot and monodansylcadaverine (MDC) staining analyses were then used to further investigate the molecular mechanisms by which luteolin protects macrophages from ox-LDL-induced foam cell formation and apoptosis. 3-Methyladenine (3-MA), an autophagy inhibitor, was used as a positive control. Results: Treatment with 25 µM luteolin not only significantly attenuated ox-LDL-induced macrophage lipid accumulation but also decreased the apoptotic rate of RAW264.7 cells, the number of TUNEL-positive macrophages and the expression of Bax, Bak, cleaved caspase-9 and cleaved caspase-3. In addition, luteolin pretreatment significantly increased autophagosome formation and Beclin-1 activity, thus increasing the ratio of LC3-II/LC3-I. Moreover, these effects were abolished by 3-MA. Conclusions: Taken together, these results highlight that luteolin treatment attenuates foam cell formation and macrophage apoptosis by promoting autophagy and provide new insights into the molecular mechanism of luteolin and its therapeutic potential in the treatment of atherosclerosis.

GW26-e4739 MaxiK Channel Responsible for Human Macrophage–derived Foam Cell Differentiation via Intracellular Ca2+ Signaling Pathway

The role of MaxiK channels in macrophage immunomodulation has been established. However, it remains unclear whether it is involved in the human macrophage-derived foam cell formation. Human peripheral blood monocytes were separated from the platelet-free blood by cell density gradient

Triterpenoid-enriched extract of Ilex kudingcha inhibits aggregated LDL-induced lipid deposition in macrophages by downregulating low density lipoprotein receptor-related protein 1 (LRP1)

Macrophage-derived foam cell formation is considered to be a critical step in the development of atherosclerosis. In the present study, we evaluated the inhibitory effect of Ilex kudingcha triterpenoid-enriched extract (TS) on foam cell formation in THP-1 macrophage cells induced by aggregated low density lipoproteins (agLDL). The inhibition of low density lipoprotein receptor-related protein 1 (LRP1) expression after TS treatment is based on mRNA and protein levels in the macrophages. These inductions were sterol regulatory element-binding protein-2 (SREBP2) dependent. On the basis of the in vitro results, the anti-atherosclerotic activity of TS was investigated in ApoE−/− mice fed a high-fat diet, ApoE−/− mice treated with TS for 6 weeks appeared to have decreased aortic sinus lesions compared with the untreated mice. These findings indicate that TS may act as an anti-atherosclerotic agent.

Wnt proteins retard macrophage foam cell formation and oxidised LDL induced apoptosis

Increased macrophage-derived foam cell formation and apoptosis are associated with atherosclerotic plaque instability. The role of Wnt proteins in foam cell formation and apoptosis is unclear. Our previous experiments demonstrated Wnt3a, Wnt4 and Wnt5a proteins in human atherosclerotic plaques. We isolated human monocytes from healthy volunteers’ blood, differentiated them into macrophages, treated concurrently with 20mg/ml oxidised LDL (Ox-LDL) and 250ng/ml Wnt proteins, and then lipid content and apoptosis were measured by oil red-O staining and cleaved caspase-3 immunocytochemistry, respectively. Recombinant Wnt3a, Wnt4 and Wnt5a significantly suppressed lipid content by 90±4%, 83±3% and 74±6%, respectively (n=4, p<0.05). In addition, treatment with recombinant Wnt3a, Wnt4 and Wnt5a significantly reduced Ox-LDL induced apoptosis by 73±7%, 63±4% and 67±10% respectively. To further investigate the effect of the Wnt proteins on lipid content and apoptosis macrophages were pre-treated with Wnt proteins or Ox-LDL for 24hours, before addition of Ox-LDL or Wnt proteins, respectively. We observed that addition of Wnt3a, Wnt4 and Wnt5a proteins for 24hours before Ox-LDL treatment retained the protective effect on lipid uptake, reducing it by 44±9%, 57%±3% and 50±3%, respectively (n=4, p<0.05). In addition Ox-LDL induced apoptosis was also reduced in a similar manner to concurrent treatment, reducing it by 54±7%, 60±9% and 62±6% respectively (n=4, p<0.05). Conversely when Ox-LDL was given before Wnts their protective effects, both on uptake and apoptosis, were not observed. In summary this suggests that these Wnt proteins may have profound effects on foam cell formation and apoptosis, in particular modulating Ox-LDL uptake rather than lipid clearance.

D4F alleviates macrophage-derived foam cell apoptosis by inhibiting CD36 expression and ER stress-CHOP pathway

This study was designed to explore the protective effect of D4F, an apoA-I mimetic peptide, on oxidized LDL (ox-LDL)-induced endoplasmic reticulum (ER) stress-CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) pathway-mediated apoptosis in macrophages. Our results showed that treating apoE knockout mice with D4F decreased the serum ox-LDL level and apoptosis in atherosclerotic lesions with concomitant downregulation of cluster of differentiation 36 (CD36) and inhibition of ER stress. In vitro, D4F inhibited macrophage-derived foam cell formation. Furthermore, like ER stress inhibitor 4-phenylbutyric acid (PBA), D4F inhibited ox-LDL- or tunicamycin (TM, an ER stress inducer)-induced reduction in cell viability and increase in lactate dehydrogenase leakage, caspase-3 activation, and apoptosis. Additionally, like PBA, D4F inhibited ox-LDL- or TM-induced activation of ER stress response as assessed by the reduced nuclear translocation of activating transcription factor 6 and the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α, as well as the downregulation of glucose-regulated protein 78 and CHOP. Moreover, D4F mitigated ox-LDL uptake by macrophages and CD36 upregulation induced by ox-LDL or TM. These data indicate that D4F can alleviate the formation and apoptosis of macrophage-derived foam cells by suppressing CD36-mediated ox-LDL uptake and subsequent activation of the ER stress-CHOP pathway.

Effect of ferulic acid on cholesterol efflux in macrophage foam cell formation and potential mechanism

The formation of macrophage-derived foam cells is a typical feature of atherosclerosis (AS). Reverse cholesterol efflux (RCT) is one of important factors for the formation of macrophage foam cells. In this study, macrophage form cells were induced by oxidized low density lipoprotein (ox-LDL) and then treated with different concentrations of ferulic acid, so as to observe the effect of ferulic acid on the intracellular lipid metabolism in the ox-LDL-induced macrophage foam cell formation, the cholesterol efflux and the mRNA expression and protein levels of ATP binding cassette transporter A1 (ABCA1) and ATP binding cassette transporter G1 (ABCG1) that mediate cholesterol efflux, and discuss the potential mechanism of ferulic acid in resisting AS. According to the findings, compared with the control group, the ox-LDL-treated group showed significant increase in intracellular lipid content, especially for the cholesterol content; whereas the intracellular lipid accumulation markedly decreased, after the treatment with ferulic acid. The data also demonstrated that the mRNA and protein expressions of ABCA1 and ABCG1 significantly increased after macrophage foam cells were treated with different concentrations of ferulic acid. In summary, ferulic acid may show the anti-atherosclerosis effect by increasing the surface ABCA1 and ABCG1 expressions of macrophage form cells and promoting cholesterol efflux.

Polydatin Inhibits Formation of Macrophage-Derived Foam Cells

Rhizoma Polygoni Cuspidati, a Chinese herbal medicine, has been widely used in traditional Chinese medicine for a long time. Polydatin, one of the major active ingredients in Rhizoma Polygoni Cuspidati, has been recently shown to possess extensive cardiovascular pharmacological activities. In present study, we examined the effects of Polydatin on the formation of peritoneal macrophage-derived foam cells in Apolipoprotein E gene knockout mice (ApoE−/−) and explored the potential underlying mechanisms. Peritoneal macrophages were collected from ApoE−/− mice and cultured in vitro. These cells sequentially were divided into four groups: Control group, Model group, Lovastatin group, and Polydatin group. Our results demonstrated that Polydatin significantly inhibits the formation of foam cells derived from peritoneal macrophages. Further studies indicated that Polydatin regulates the metabolism of intracellular lipid and possesses anti-inflammatory effects, which may be regulated through the PPAR-γ signaling pathways.

Traditional Chinese Medicine and Vascular Disease.

Traditional Chinese Medicine and Vascular Disease.

Autocrine Human Urotensin II Enhances Macrophage-Derived Foam Cell Formation in Transgenic Rabbits.

Circulating urotensin II (UII) is involved in the development of atherosclerosis. However, the role of autocrine UII in the development of atherosclerosis remains unclear. Here, we tested the hypothesis that autocrine UII would promote atherosclerosis. Transgenic rabbits were created as a model to study macrophage-specific expressing human UII (hUII) and used to investigate the role of autocrine UII in the development of atherosclerosis. Transgenic rabbits and their nontransgenic littermates were fed a high cholesterol diet to induce atherosclerosis. Comparing the transgenic rabbits with their nontransgenic littermates, it was observed that hUII expression increased the macrophage-positive area in the atherosclerotic lesions by 45% and the positive area ratio by 56% in the transgenic rabbits. Autocrine hUII significantly decreased the smooth muscle cell-positive area ratio in transgenic rabbits (by 54%), without affecting the plasma levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and glucose and adipose tissue contents. These results elucidated for the first time that autocrine UII plays an important role in the development of atherosclerosis by increasing the accumulation of macrophage-derived foam cell.