scholarly journals Amelioration of atherosclerosis in apolipoprotein E-deficient mice by inhibition of lipoprotein-associated phospholipase A2

2013 ◽  
Vol 36 (1) ◽  
pp. 32 ◽  
Author(s):  
Hui Zhang ◽  
Jin-Ying Zhang ◽  
Tong-Wen Sun ◽  
De-Liang Shen ◽  
Fei He ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Apolipoprotein E ◽  
Inflammatory Cytokines ◽  
Negative Control ◽  
Therapeutic Effects ◽  
Inflammatory Gene Expression ◽  
Plaque Area ◽  
Atherosclerotic Lesions ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

Purpose: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is involved in the pathogenesis of atherosclerosis, especially in advanced plaques. In the present study, the abilities of darapladib, a selective Lp-PLA2 inhibitor, and lentivirus-mediated Lp-PLA2 silencing on inflammation and atherosclerosis in apolipoprotein E-deficient mice were compared. Methods: Apolipoprotein E-deficient mice were fed on a high-fat diet and a constrictive collar was placed around the left carotid artery to induce plaque formation. The mice were randomly divided into control, negative control (NC), darapladib and RNA interference (RNAi) groups. Eight weeks after surgery, lentivirus-mediated RNAi construct or darapladib were used to decrease the expression of Lp-PLA2. Plaques were collected five weeks later for histological analysis. Inflammatory gene expression in the atherosclerotic lesions were then determined at the mRNA and protein level. Results: The expression of pro-inflammatory cytokines was significantly reduced in the treatment group, compared to nontreatment group, whereas the plasma concentration of anti-inflammatory cytokines increased markedly. Moreover, our results demonstrated a significant reduction in plaque lipid content, as well as a rise in collagen content following Lp-PLA2 inhibition. Interestingly, when comparing the two methods of Lp-PLA2 inhibition, animals treated with Lp-PLA2 RNAi were found to exhibit lower plaque areas and enhanced improvement of plaque stability as compared with animals treated with darapladib. Darapladib had no attenuating effect on atherosclerotic plaque area. These therapeutic effects were independent of plasma lipoprotein levels. Conclusions: Lp-PLA2 inhibition by darapladib or lentivirus-mediated RNAi ameliorated inflammation and atherosclerosis in apolipoprotein E-deficient mice. The effect was more prominent in the RNAi group.

Abstract 252: Interleukin-27 Signaling Regulates Myeloid Cells Activation in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Iuliia Peshkova ◽  
Aliia Fatkhullina ◽  
Ekaterina Koltsova
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Antigen Presenting Cells ◽  
Atherosclerotic Lesions ◽  
Mediators Of Inflammation ◽  
Antigen Presenting ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

Atherosclerosis is a lipid-driven inflammatory disease characterized by the progressive plaque growth in the vessels. Cytokines are important mediators of inflammation and atherosclerosis. While pro-inflammatory cytokines were extensively investigated, little is known about the role of anti-inflammatory cytokines as to their ability to control vascular inflammation. We tested whether immunoregulatory IL-27R signaling is important to control inflammation in mouse models of atherosclerosis. We found that atherosclerosis-prone mice with hematopoietic deficiency of IL-27R ( Ldlr -/- mice reconstituted with bone marrow from Il27ra -/- ) or global deficiency ( Il27ra -/- x Apoe -/- ) developed significantly larger atherosclerotic lesions compared to controls. Atherosclerotic lesions in IL-27R deficient mice contained more CD45 + leukocytes and CD4 + T cells, which produced pro-atherogenic cytokines IL-17A and TNF-α. These cytokines normally suppressed by IL-27, regulated the expression of CCL2 and other chemokines, which in turn led to accumulation of myeloid CD11b + and CD11c + cells in atherosclerotic aortas. Using two-photon microscopy, we found enhanced interactions between antigen presenting cells and T cells in the aortas of IL-27R deficient mice accompanied by enhanced CD4 T cell proliferation. Moreover, macrophages in Il27ra -/- aortas also demonstrated enhanced ability to produce pro-inflammatory cytokines, including IL-1. The blockade of IL-1R signaling, however, strongly suppressed atherosclerosis progression in IL-27R deficient but not control mice, suggesting an important role of IL-27 in the regulation of IL-1 production in atherosclerosis. Overall, our data demonstrate that IL-27R signaling in atherosclerosis is required to control function of antigen presenting cells modulating subsequent T cell activation in the aortas. Moreover, it controls macrophage activation and pro-inflammatory myeloid cell-derived cytokine production. These mechanisms altogether curb pathogenic T cell lineage differentiation and, thus, atherosclerosis, suggesting potent anti-atherogenic role of IL-27.

scholarly journals Moxibustion at CV4 alleviates atherosclerotic lesions through activation of the LXRα/ABCA1 pathway in apolipoprotein-E-deficient mice

2019 ◽  
Vol 37 (4) ◽  
pp. 237-243 ◽  
Author(s):  
Yingxue Cui ◽  
Juntian Liu ◽  
Chang Huang ◽  
Baixiao Zhao
Keyword(s):  
Apolipoprotein E ◽  
Thoracic Aorta ◽  
Serum Lipids ◽  
Plaque Area ◽  
Atherosclerotic Lesions ◽  
Liver X Receptor Α ◽  
Moxa Stick ◽  
And Control ◽  
Area Percentage ◽  
Deficient Mice

Objectives: To investigate the anti-atherogenic effect of moxibustion and whether it is mediated through the reverse cholesterol transport process. Methods: 8-week-old male apolipoprotein E deficient (ApoE−/− knockout) mice were randomly divided into two groups (n=10 per group): atherosclerosis (AS) and AS plus moxibustion (AS+M). C57BL/6J mice of the same background (n=10) were selected as controls. Mice in the AS+M group received indirect moxibustion with an ignited moxa stick held over CV4. Mice of the AS and control groups were restrained in the same holder with an unlit moxa stick held over CV4. All treatments were performed for 20 min per day, 6 days per week for 12 weeks. After the treatment, the mice were euthanased and their serum lipids were measured. The aortic roots and thoracic aortas were collected for haematoxylin and eosin and red oil O staining, respectively, to analyse the atherosclerotic lesions. Expression of adenosine triphosphate binding cassette (ABCA)A1/G1 and liver X receptor α (LXRα) in the thoracic aorta were examined with Western blotting. Results: The moxibustion-treated (AS+M) mice showed a significantly lower plaque area percentage in the aortic root and thoracic aorta, and higher expression of LXRα and ABCA1 in the thoracic aorta compared with the AS mice. No significant differences were found in average lipid area percentage in the thoracic aorta, or ABCG1 expression in the thoracic aorta, between mice in the AS+M and AS groups. Conclusion: Moxibustion treatment at CV4 suppressed the progression of atherosclerotic lesions in ApoE−/− mice. The anti-atherogenic effect of moxibustion may be achieved by: (1) regulation of lipid metabolism, and thus prevention of lipid accumulation; and (2) upregulation of LXRα- and ABCA1-mediated cholesterol efflux in the lesion area.

scholarly journals Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samira Ahmadvand Koohsari ◽  
Abdorrahim Absalan ◽  
Davood Azadi
Keyword(s):  
Spinal Cord ◽  
Body Weight ◽  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Clinical Score ◽  
Human Umbilical Cord ◽  
Therapeutic Effects ◽  
Leukocyte Infiltration ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

AbstractThe therapeutic effects of mesenchymal stem cells-extracellular vesicles have been proved in many inflammatory animal models. In the current study, we aimed to investigate the effect of extracellular vesicles (EVs) derived from human umbilical cord-MSC (hUCSC-EV) on the clinical score and inflammatory/anti-inflammatory cytokines on the EAE mouse model. After induction of EAE in C57Bl/6 mice, they were treated intravenously with hUCSC-EV or vehicle. The clinical score and body weight of all mice was registered every day. On day 30, mice were sacrificed and splenocytes were isolated for cytokine assay by ELISA. Cytokine expression of pro-/anti-inflammatory cytokine by real-time PCR, leukocyte infiltration by hematoxylin and eosin (H&E) staining, and the percent of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) positive cells by immunohistochemistry were assessed in the spinal cord. Our results showed that hUCSC-EV-treated mice have lower maximum mean clinical score (MMCS), pro-inflammatory cytokines, and inflammatory score in comparison to the control mice. We also showed that hUCSC-EV administration significantly improved body weight and increased the anti-inflammatory cytokines and the frequency of Treg cells in the spleen. There was no significant difference in the percent of GFAP and MBP positive cells in the spinal cord of experimental groups. Finally, we suggest that intravenous administration of hUCSC-EV alleviate induce-EAE by reducing the pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, and increasing the anti-inflammatory cytokines, IL-4 and IL-10, and also decrease the leukocyte infiltration in a model of MS. It seems that EVs from hUC-MSCs have the same therapeutic effects similar to EVs from other sources of MSCs, such as adipose or bone marrow MSCs.

scholarly journals Amelioration of atherosclerosis in apolipoprotein E-deficient mice by combined RNA interference of lipoprotein-associated phospholipase A2 and YKL-40

PLoS ONE ◽  
2018 ◽  
Vol 13 (8) ◽  
pp. e0202797 ◽  
Author(s):  
Hui Zhang ◽  
Wenping Zhou ◽  
Chang Cao ◽  
Wenjing Zhang ◽  
Gangqiong Liu ◽  
...  
Keyword(s):  
Rna Interference ◽  
Phospholipase A2 ◽  
Apolipoprotein E ◽  
Deficient Mice

Macrophage P53 controls foam cell death in atherosclerotic lesions of apolipoprotein E deficient mice

2006 ◽  
Vol 45 (3) ◽  
pp. e4
Author(s):  
Marion J.J. Gijbels ◽  
Lianne S.M. Boesten ◽  
A. Suzanne M. Zadelaar ◽  
Aart G. Jochemsen ◽  
Bob van de Water ◽  
...  
Keyword(s):  
Cell Death ◽  
Apolipoprotein E ◽  
Foam Cell ◽  
Atherosclerotic Lesions ◽  
Deficient Mice

Abstract 424: Phospholipid Transfer Protein Deficiency Promotes Inflammatory Factors' Expression via TLR4-TAK1-NFκB Pathway in Macrophage

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Yang Yu
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Factors ◽  
Phospholipid Transfer Protein ◽  
Wild Type ◽  
Transfer Protein ◽  
Phospholipid Transfer ◽  
Nfκb Pathway ◽  
Nuclear Levels ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

Phospholipid transfer protein (PLTP) plays important roles in macrophage mediated inflammation. In the current study we observed that endogenous PLTP modulated pro-inflammatory pathways in macrophage. With the presence of LPS, peritoneal derived macrophage (PDM) or bone marrow derived macrophage (BMDM) from PLTP deficient mice (PLTP-/-) expressed significantly higher level of pro-inflammatory cytokines compared with PDM or BMDM from wild-type mice (WT), respectively. LPS induced TNFα expression in PLTP-/- BMDM or PLTP knockdown RAW264.7 were suppressed by (5Z)-7-Oxozeaenol, a TAK1 inhibitor, suggesting PLTP deficiency enhanced the expression of pro-inflammatory cytokines via TAK1-NFκB pathway in macrophage. Furthermore, abundance of TLR4 on the membrane was dramatically increased in BMDM from PLTP-/- compared with WT. In addition, inhibition of ABCA1 by chemical inhibitor, glyburide, did not reduce nuclear levels of active STAT3 of BMDM, which indicated that no autocrine PLTP triggered ABCA1-JAK2-STAT3 pathway in this study. In conclusion, PLTP deficiency or low expression may enhance LPS induced pro-inflammatory cytokines expression via TLR4-TAK1-NFκB pathway in macrophage.

scholarly journals Pycnogenol protects against diet-induced hepatic steatosis in apolipoprotein-E-deficient mice

2018 ◽  
Vol 315 (2) ◽  
pp. E218-E228 ◽  
Author(s):  
Difei Wang ◽  
Huiying Cong ◽  
Xiaoli Wang ◽  
Yanli Cao ◽  
Shoichiro Ikuyama ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Apolipoprotein E ◽  
Hepatic Steatosis ◽  
Inflammatory Cytokines ◽  
Lipid Content ◽  
Acid Uptake ◽  
Short Term Treatment ◽  
Hepatic Lipid ◽  
Deficient Mice ◽  
Hepatic Lipid Content

PycnogenolR (PYC), a combination of active flavonoids derived from French maritime pine bark, is a natural antioxidant that has various pharmacological activities. Here, we investigated the beneficial effect of PYC on diet-induced hepatic steatosis. Apolipoprotein E (ApoE)-deficient male mice were administered PYC at oral doses of 30 or 100 mg·kg−1·day−1 for 2 wk in advance and were then fed a high-cholesterol and -fat diet (HCD) for 8 wk. Biochemical, immunohistochemical, and gene expression analyses were conducted to explore the effect of PYC on lipid metabolism in ApoE-deficient mice on a HCD. Short-term treatment with HCD in ApoE-deficient mice induced hepatic injuries, such as lipid metabolism disorder and hepatic histopathological changes. We found that PYC reduced body weight and the increase of serum lipids that had been caused by HCD. Supplementation of PYC significantly reduced lipid deposition in the liver, as shown by the lowered hepatic lipid content and histopathological lesions. We subsequently detected genes related to lipid metabolism and inflammatory cytokines. The study showed that PYC markedly suppressed the expression of genes related to hepatic lipogenesis, fatty acid uptake, and lipid storage while increasing the lipolytic gene, which thus reduced hepatic lipid content. Furthermore, PYC mainly reduced the expression of inflammatory cytokines and the infiltration of inflammatory cells, which were resistant to the development of hepatic steatosis. These results demonstrate that PYC protects against the occurrence and development of hepatic steatosis and may provide a new prophylactic approach for nonalcoholic fatty liver disease (NAFLD).

Abstract 276: Systemic Delivery of Microrna-146a Improves Endothelial Function and Ameliorates Atherosclerosis in Apolipoprotein E-deficient Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Shuangtao Ma ◽  
Xiao Yu Tian ◽  
Chaofeng Mu ◽  
Haifa Shen ◽  
Yunrong Zhang ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Apolipoprotein E ◽  
Carotid Arteries ◽  
Treated Group ◽  
Vehicle Group ◽  
Early Event ◽  
Aortic Tissue ◽  
Systemic Delivery ◽  
Plaque Area ◽  
Deficient Mice

Rationale: Endothelial inflammation is an early event in the development of atherosclerosis. The microRNA (miR)-146a showed anti-inflammatory effects in cultured endothelial cells. In this study, we investigated the therapeutic role of miR-146a in endothelial function and atherosclerosis in apolipoprotein E (ApoE)-deficient mice. Methods and Results: The miR-146a was packaged into a multistage vector (MSV) that was conjugated with an E-selectin-targeting thioaptamer (ESTA) to form an ESTA-MSV microparticle. The ApoE-deficient mice were fed with Western diet and injected through tail vein with 15μg of miR-146a loaded ESTA-MSV microparticles or vehicle vectors biweekly for 12 weeks. The expressions of miR-146a in aortic tissue was increased by five times at two weeks after injection. However, the expressions of miR-146a in heart, lung, liver, spleen, kidney, and skeletal muscle were not increased. The acetylcholine-induced endothelium-dependent relaxations in both carotid arteries and aortas were significantly improved in mice from miR-146a treated group compared with vehicle group. In addition, the endothelium-dependent contractions of carotid arteries were also improved by miR-146a treatment. The en face oil red O staining of whole aortas showed the plaque area was decreased in miR-146a-treated mice. Application of miR-146a also decreased the plaque size, macrophages, and T-lymphocytes, but increased the collagen deposition and vascular smooth muscle cells in the sections of aortic roots. The PCR results showed that expressions of chemokine (C-C motif) ligand (CCL)-2, CCL-5, and CCL-8 were decreased by miR-146a. Conclusions: E-selectin-targeting delivery of miR-146a improves endothelial function and inhibits atherosclerosis.

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