Abstract 141: The Loss of Nrf2 Enhances Vascular Inflammation but Reduces Atherosclerosis via Effects on Plasma Lipids in LDL Receptor Deficient Mice Fed High Fat Diet

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Anna-Kaisa Ruotsalainen ◽  
Emmi Tapper ◽  
Jari Lappalainen ◽  
Seppo Ylä-Herttuala ◽  
Anna-Liisa Levonen
Keyword(s):  
Bone Marrow ◽  
High Fat Diet ◽  
Foam Cell ◽  
Ldl Receptor ◽  
Total Loss ◽  
Foam Cell Formation ◽  
Systemic Effects ◽  
Related Factor ◽  
High Fat ◽  
Deficient Mice

OBJECTIVE Transcription factor NF-E2-related factor 2 (Nrf2) regulates antioxidant and detoxifying enzymes affording cytoprotection in the cardiovascular system. We have previously reported that Nrf2 deficiency specific to bone marrow derived cells aggravates atherosclerosis in LDL receptor deficient (LDLR-/-) mice. Furthermore, Nrf2 deficiency in macrophages enhances foam cell formation and promotes the proinflammatory phenotype. In contrast, the total loss of Nrf2 has been shown to protect against atherogenesis in apoE-deficient mice. The mechanism by which Nrf2 deficiency affords atheroprotection in apoE-model is currently unknown, but combined systemic and local vascular effects have been proposed. Given these contrasting results, we aimed at assessing the effect of total loss of Nrf2 on atherogenesis in hypercholesterolemic LDLR-/- mice. METHODS AND RESULTS Nrf2-/- mice were cross-bred to LDLR-/- mice and fed a high fat diet (HFD) for 6 or 12 weeks. The degree of atherosclerosis was assessed from the cross-sections of proximal aorta. Nrf2 deficiency decreased atherosclerosis in females from 17.2±8.7 % (mean ±SD, n=11-25) to 12.3±4.6 % (p=0.1) and in males from 11.2±3.9 % to 7.6±4.6 % (p=0.025) after 6 weeks on HFD. After 12 weeks on HFD the effects were more pronounced, as Nrf2 deficiency decreased atherosclerosis from 36.5±5.5 % to 30.3±3.5 % in females (p=0.001) and from 30.6±5.7 % to 21.3±6.9 % in males (p=0.005). Nrf2 deficiency also increased the macrophage content relative to lesion area. Supporting systemic effects, Nrf2 deficiency reduced plasma total cholesterol from 24.0±8.4 mmol/l to 10.6±6,7 mmol/l (p=0.006) and triglyceride levels from 3.6±1.4 mmol/l to 1.7±1.2 mmol/l (p=0.008) in males after 6 weeks on HFD. CONCLUSIONS In contrast to bone marrow specific Nrf2 deficiency, total loss of Nrf2 aggravates atherosclerosis in LDLR-/- mice likely via systemic effects on lipid metabolism.

Abstract 451: Bone Marrow-derived Matricellular Protein CCN3 is Protective Against Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Chao Zhang ◽  
Xingjian Hu ◽  
Hong Shi ◽  
Wenconghui Wu ◽  
Yulan Qing ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Fat Diet ◽  
Immune Cell ◽  
Foam Cell ◽  
Reactive Oxygen Species Generation ◽  
Developed Countries ◽  
Foam Cell Formation ◽  
Matricellular Protein ◽  
High Fat ◽  
Double Knockout

Background: Atherosclerosis and its complications (myocardial infarction, stroke, peripheral vascular disease) are the major cause of morbidity and mortality in developed countries. Despite considerable efforts, the underlying pathomechanisms remain incompletely understood. In this study, we examined the role of a matricellular protein termed CCN3 in the pathogenesis of atherosclerosis. Methods and Results: To investigate whether CCN3 deficiency affects the development of atherosclerosis, control (ApoE-/-) and CCN3/ApoE double knockout mice were subjected to high fat diet feeding. In response to 16-week high fat diet feeding, the aortas of CCN3/ApoE double knockout (DKO) mice demonstrated exquisite susceptibility to atherosclerosis formation as evidenced by significantly increased size of aortic lipid-rich plaques in aortic roots, arch, thoracic and abdominal aorta. Concomitant with this, the atherosclerosis phenotype of DKO mice was manifested as follows: (1) a profoundly enhanced immune cell infiltration; (2) significantly increased expression of inflammatory markers; (3) heightened reactive oxygen species generation. Next, to address the cellular contributor(s) within or outside of the vessel wall responsible for the atherosclerosis phenotype, we performed reciprocal bone marrow transplantation (BMT) experiments. Transplantation of DKO bone marrow to ApoE-/- mice resulted in an increase of atherosclerosis formation, while transplantation of ApoE-/- marrow to DKO mice caused a reduction of atherosclerosis. These results indicate CCN3 deficiency in the bone marrow plays a major role in the development of atherosclerosis. Mechanistically, our cell-based studies in isolated macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect attributed to the modulation of key factors (e.g., increase of CD36, decrease of ABCG1) involved in lipoprotein transport. Conclusion: These results demonstrate bone marrow-derived CCN3 as an essential regulator of atherosclerosis and suggest the potential for future therapeutic strategies by manipulating CCN3 levels.

P4141Lack of IkBNS promotes cholate-containing high-fat diet-induced inflammation and atherogenesis in low-density lipoprotein (LDL) receptor-deficient mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
K Kitamura ◽  
K Isoda ◽  
K Akita ◽  
K Miyosawa ◽  
T Kadoguchi ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Aortic Root ◽  
High Fat Diet ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Endotoxin Shock ◽  
High Fat ◽  
Lps Challenge ◽  
Atherosclerotic Lesions ◽  
Deficient Mice

Abstract Background IκBNS is one of the nuclear IκB proteins and regulates a subset of Toll-like receptor (TLR) dependent genes. LPS acts as extremely strong stimulator of innate immunity. We tried to investigate whether stimulation of innate immunity could promote atherosclerosis in the IκBNS-deficient atherogenic mice. However all IκBNS-deficient mice died of LPS challenge at a dose of which almost all wild-type mice survived, because IκBNS-deficient mice are highly sensitive to LPS-induced endotoxin shock. Then, we decided to use a cholate-containing high fat diet (HFD(CA(+))), which has been widely used as an atherogenic diet in mice. Furthermore, HFD(CA(+)) has been shown to induce TLR4 mediated early inflammatory response. The present study aims to clarify the lack of IκBNS promotes atherogenesis in LDL receptor-deficient (LDLr−/−) mice fed HFD(CA(+)) compared with those fed a cholate-free HFD (HFD(CA(−)). Methods and results Mice that lacked IκBNS (IκBNS−/−) were crossed with LDLr−/− mice and formation of atherosclerotic lesions was analyzed after 6 weeks consumption of HFD(CA(+)) or HFD(CA(−)). The extent of atherosclerosis in the aorta (en face) was significantly increased in IκBNS−/−/LDLr−/−(CA(+)) mice compared with others after 6-week consumption of HFD (p<0.01) (Figure). Interestingly, HFD(CA(−)) did not induce significant atherosclerotic lesions in IκBNS−/−/LDLr−/− compared with LDLr−/− mice after 6-week consumption (Figure). Immunostaining of aortic root lesion revealed that HFD(CA(+)) significantly increased positive area of Mac-3 (macrophage) by 1.5-fold (p=0.01) and TLR4, interleukin-6 (IL-6) expression by 1.7-fold (P<0.05) and 1.5-fold (p<0.05) respectively in IκBNS−/−/LDLr−/− (CA(+)) compared to LDLr−/− (CA(+)) mice. Furthermore, active STAT3 (pSTAT3)-positive cells were significantly increased by 1.7-fold in the atherosclerotic lesions of IκBNS−/−/LDLr−/− (CA(+)) compared with LDLr−/− (CA(+)) mice (p<0.01). TLR4 positive areas, IL-6 positive areas, and pSTAT3 positive cells were overlapped with Mac-3, indicating that TLR4-IL-6-STAT3 axis was activated in macrophages in IκBNS−/−/LDLr−/− (CA(+)) mice. On the other hand, HFD(CA(−)) could not induce any difference in these immunoreactivities of arteriosclerotic lesions between IκBNS−/−/LDLr−/− (CA(−)) compared with LDLr−/− (CA(−)) mice. These findings suggest that IκBNS deficiency and HFD(CA(+)) promote atherogenesis in LDLr−/− mice via TLR4/IL-6/STAT3 pathway. Finally, we show the monocytes from peripheral blood of IκBNS−/−/LDLr−/− (CA(+)) mice were found to contain the most mounts of Ly6Chi among four groups, suggesting that lack of IκBNS enhances inflammation in the response HFD(CA(+)) feeding and thereby influence atherogenesis in IκBNS−/−/LDLr−/− mice. Aortic root atherosclerotic lesions Conclusions The present study is the first to demonstrate that the activation of innate immune system using HFD(CA(+)) induced significant inflammation and atherogenesis in IκBNS−/−/LDLr−/− compared with LDLr−/− mice.

scholarly journals Cysteamine Decreases Low‐Density Lipoprotein Oxidation, Causes Regression of Atherosclerosis, and Improves Liver and Muscle Function in Low‐Density Lipoprotein Receptor–Deficient Mice

2021 ◽  
Vol 10 (18) ◽  
Author(s):  
Feroz Ahmad ◽  
Robert D. Mitchell ◽  
Tom Houben ◽  
Angela Palo ◽  
Tulasi Yadati ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
High Fat Diet ◽  
Muscle Function ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
High Fat ◽  
Atherosclerotic Lesions ◽  
Deficient Mice

Background We have shown previously that low‐density lipoprotein (LDL) can be oxidized in the lysosomes of macrophages, that this oxidation can be inhibited by cysteamine, an antioxidant that accumulates in lysosomes, and that this drug decreases atherosclerosis in LDL receptor–deficient mice fed a high‐fat diet. We have now performed a regression study with cysteamine, which is of more relevance to the treatment of human disease. Methods and Results LDL receptor–deficient mice were fed a high‐fat diet to induce atherosclerotic lesions. They were then reared on chow diet and drinking water containing cysteamine or plain drinking water. Aortic atherosclerosis was assessed, and samples of liver and skeletal muscle were analyzed. There was no regression of atherosclerosis in the control mice, but cysteamine caused regression of between 32% and 56% compared with the control group, depending on the site of the lesions. Cysteamine substantially increased markers of lesion stability, decreased ceroid, and greatly decreased oxidized phospholipids in the lesions. The liver lipid levels and expression of cluster of differentiation 68, acetyl–coenzyme A acetyltransferase 2, cytochromes P450 (CYP)27, and proinflammatory cytokines and chemokines were decreased by cysteamine. Skeletal muscle function and oxidative fibers were increased by cysteamine. There were no changes in the plasma total cholesterol, LDL cholesterol, high‐density lipoprotein cholesterol, or triacylglycerol concentrations attributable to cysteamine. Conclusions Inhibiting the lysosomal oxidation of LDL in atherosclerotic lesions by antioxidants targeted at lysosomes causes the regression of atherosclerosis and improves liver and muscle characteristics in mice and might be a promising novel therapy for atherosclerosis in patients.

scholarly journals Dapagliflozin decreases atherosclerotic plaque instability via regulating macrophage pyroptosis

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
L Xu ◽  
Y Dai ◽  
K Yao ◽  
H Yang ◽  
A Sun ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Atherosclerotic Plaque ◽  
High Fat Diet ◽  
Foam Cell ◽  
Atherosclerotic Lesion ◽  
Plaque Formation ◽  
Public Institution ◽  
Foam Cell Formation ◽  
Diabetic Patients ◽  
High Fat

Abstract Background Vulnerable plaques are characterized by infiltration of inflammatory cells, playing a key role in the progression of acute coronary events. It's important to clarify the inflammatory mechanism of unstable plaque formation. Several clinical trials have demonstrated that dapagliflozin could reduce major adverse cardiac events in whether diabetic or non-diabetic patients. However, the underlying cardioprotective mechanism of dapagliflozin remains unclear. This study was aimed to investigate the role of dapagliflozin in regulating macrophage pyroptosis and vulnerable plaque formation. Methods 20 ApoE−/− mice (control) were fed with high fat diet while another 20 ApoE−/− mice were challenged with high fat diet plus dapagliflozin for 12 weeks. The extent and instability of atherosclerotic plaque was determined by oil-red staining, HE staining, immunofluorescence staining and electron microscopy. Changes in subsets of immune cells were evaluated by flow cytometry. Plasma cytokines were assessed by ELISA. Microarray analysis was applied to detect gene expressions while Western blot and real-time PCR was used to assess gene expression levels. Results Morphology studies revealed that dapagliflozin could inhibit plaque formation and reduce instability in ApoE−/− mice. FACS data showed that dapagliflozin could decrease CD11b+Ly6Chigh M1 macrophages differentiation and inhibit foam cells formation in ApoE−/− mice. Microarray analysis and in vitro studies exhibited that dapagliflozin could induce the down regulation of NLRP3, caspase-1, IL-1β, IL-18 and MMP-7/10/12/14 to retard macrophage pyroptosis and foam cell formation. Conclusions We have characterized a novel role for dapagliflozin in modulating atherosclerotic lesion development and progression. We envision that this study may provide several potential therapeutic targets for treatment of acute coronary syndromes. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Shanghai Sailing Program

Curcumin modulation of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice

2014 ◽  
Vol 232 (1) ◽  
pp. 40-51 ◽  
Author(s):  
S.T. Hasan ◽  
J.-M. Zingg ◽  
P. Kwan ◽  
T. Noble ◽  
D. Smith ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Ldl Receptor ◽  
High Fat ◽  
Deficient Mice

scholarly journals 12-Hydroxyeicosapentaenoic acid inhibits foam cell formation and ameliorates high-fat diet-induced pathology of atherosclerosis in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takahiro Nagatake ◽  
Yuki Shibata ◽  
Sakiko Morimoto ◽  
Eri Node ◽  
Kento Sawane ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Foam Cell ◽  
Linseed Oil ◽  
Cell Formation ◽  
Chronic Inflammatory Disease ◽  
Foam Cell Formation ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
High Fat ◽  
The Impact

AbstractAtherosclerosis is a chronic inflammatory disease associated with macrophage aggregate and transformation into foam cells. In this study, we sought to investigate the impact of dietary intake of ω3 fatty acid on the development of atherosclerosis, and demonstrate the mechanism of action by identifying anti-inflammatory lipid metabolite. Mice were exposed to a high-fat diet (HFD) supplemented with either conventional soybean oil or α-linolenic acid-rich linseed oil. We found that as mice became obese they also showed increased pulsatility and resistive indexes in the common carotid artery. In sharp contrast, the addition of linseed oil to the HFD improved pulsatility and resistive indexes without affecting weight gain. Histological analysis revealed that dietary linseed oil inhibited foam cell formation in the aortic valve. Lipidomic analysis demonstrated a particularly marked increase in the eicosapentaenoic acid-derived metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) in the serum from mice fed with linseed oil. When we gave 12-HEPE to mice with HFD, the pulsatility and resistive indexes was improved. Indeed, 12-HEPE inhibited the foamy transformation of macrophages in a peroxisome proliferator-activated receptor (PPAR)γ-dependent manner. These results demonstrate that the 12-HEPE-PPARγ axis ameliorates the pathogenesis of atherosclerosis by inhibiting foam cell formation.

scholarly journals Lack of IκBNS promotes cholate-containing high-fat diet-induced inflammation and atherogenesis in low-density lipoprotein (LDL) receptor-deficient mice

2019 ◽  
Vol 23 ◽  
pp. 100344
Author(s):  
Kenichi Kitamura ◽  
Kikuo Isoda ◽  
Koji Akita ◽  
Katsutoshi Miyosawa ◽  
Tomoyasu Kadoguchi ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
High Fat ◽  
Deficient Mice
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