scholarly journals Atherosclerotic plaque vulnerability is increased in mouse model of lupus

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Marie-Laure Santiago-Raber ◽  
Fabrizio Montecucco ◽  
Nicolas Vuilleumier ◽  
Kapka Miteva ◽  
Daniela Baptista ◽  
...  
Keyword(s):  
Mouse Model ◽  
Atherosclerotic Plaque ◽  
Lupus Erythematosus ◽  
Atherosclerotic Lesion ◽  
Neutrophil Infiltration ◽  
Lesion Size ◽  
High Cholesterol Diet ◽  
Mrna Levels ◽  
Plaque Vulnerability ◽  
Plaque Destabilization

Abstract Anti-apolipoprotein A-1 (anti-apoA-1 IgG) and anti-double stranded DNA (anti-dsDNA IgG) autoantibodies have been described as mediators of atherogenesis in mice and humans. In the present study, we aim to investigate the association between atherosclerotic parameters, autoantibodies and plaque vulnerability in the context of systemic lupus erythematosus (SLE). We therefore bred a lupus prone-mouse model (Nba2.Yaa mice) with Apoe−/− mice resulting in Apoe−/−Nba2.Yaa mice spontaneously producing anti-apoA-1 IgG antibodies. Although Apoe−/−Nba2.Yaa and Apoe−/− mice subject to a high cholesterol diet displayed similar atherosclerosis lesions size in aortic roots and abdominal aorta, the levels of macrophage and neutrophil infiltration, collagen, MMP-8 and MMP-9 and pro-MMP-9 expression in Apoe−/−Nba2.Yaa mice indicated features of atherosclerotic plaque vulnerability. Even though Apoe−/−Nba2.Yaa mice and Apoe−/− mice had similar lipid levels, Apoe−/−Nba2.Yaa mice showed higher anti-apoA-1 and anti-dsDNA IgG levels. Apoe−/−Nba2.Yaa mice displayed a reduction of the size of the kidney, splenomegaly and lymph nodes (LN) hypertrophy. In addition, anti-apoA-1 and anti-dsDNA IgG increased also in relation with mRNA levels of GATA3, IL-4, Bcl-6 and CD20 in the spleen and aortic arch of Apoe−/−Nba2.Yaa mice. Our data show that although atherosclerosis-lupus-prone Apoe−/−Nba2.Yaa mice did not exhibit exacerbated atherosclerotic lesion size, they did show features of atherosclerotic plaque destabilization in correlation with the increase of pro-atherogenic autoantibodies.

scholarly journals Intermedin1-53 attenuates atherosclerotic plaque vulnerability by inhibiting CHOP-mediated apoptosis and inflammasome in macrophages

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Jin-Ling Ren ◽  
Yao Chen ◽  
Lin-Shuang Zhang ◽  
Ya-Rong Zhang ◽  
Shi-Meng Liu ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Atherosclerotic Lesion ◽  
Immunohistochemical Analysis ◽  
Inhibitory Effect ◽  
Lesion Size ◽  
Plaque Vulnerability ◽  
Macrophage Apoptosis ◽  
Advanced Lesion

AbstractAtherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture of atherosclerotic plaque, and endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis. Intermedin (IMD) is a regulator of ERS. Here, we investigated whether IMD enhances atherosclerotic plaque stability by inhibiting ERS-CHOP-mediated apoptosis and subsequent inflammasome in macrophages. We studied the effects of IMD on features of plaque vulnerability in hyperlipemia apolipoprotein E-deficient (ApoE−/−) mice. Six-week IMD1-53 infusion significantly reduced atherosclerotic lesion size. Of note, IMD1-53 lowered lesion macrophage content and necrotic core size and increased fibrous cap thickness and vascular smooth muscle cells (VSMCs) content thus reducing overall plaque vulnerability. Immunohistochemical analysis indicated that IMD1-53 administration prevented ERS activation in aortic lesions of ApoE−/− mice, which was further confirmed in oxidized low-density lipoproteins (ox-LDL) induced macrophages. Similar to IMD, taurine (Tau), a non-selective ERS inhibitor significantly reduced atherosclerotic lesion size and plaque vulnerability. Moreover, C/EBP-homologous protein (CHOP), a pro-apoptosis transcription factor involved in ERS, was significantly increased in advanced lesion macrophages, and deficiency of CHOP stabilized atherosclerotic plaques in AopE−/− mice. IMD1-53 decreased CHOP level and apoptosis in vivo and in macrophages treated with ox-LDL. In addition, IMD1-53 infusion ameliorated NLRP3 inflammasome and subsequent proinflammatory cytokines in vivo and in vitro. IMD may attenuate the progression of atherosclerotic lesions and plaque vulnerability by inhibiting ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation. The inhibitory effect of IMD on ERS-induced macrophages apoptosis was probably mediated by blocking CHOP activation.

scholarly journals Activation of Bone Marrow-Derived Cells Angiotensin (Ang) II Type 1 Receptor by Ang II Promotes Atherosclerotic Plaque Vulnerability

2018 ◽  
Vol 19 (9) ◽  
pp. 2621
Author(s):  
Maxime Pellegrin ◽  
Karima Bouzourène ◽  
Jean-François Aubert ◽  
Aimable Nahimana ◽  
Michel Duchosal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mrna Expression ◽  
Atherosclerotic Plaque ◽  
Cholesterol Metabolism ◽  
Mrna Levels ◽  
Ang Ii ◽  
Plaque Vulnerability ◽  
Plaque Development ◽  
Pro Inflammatory Cytokines

Angiotensin (Ang) II triggers vulnerable atherosclerotic plaque development. Bone marrow (BM)-derived cells are key players in atherogenesis but whether Ang II induces plaque vulnerability directly through Ang II type 1 receptor (AT1R) activation on these cells remains to be clarified. In the present study, we investigated whether a lack of AT1R on BM-derived cells might affect Ang II-mediated vulnerable plaque development. The 2-kidney, 1-clip (2K1C) model (Ang II-dependent mouse model of advanced atherosclerosis and vulnerable plaques) was generated in ApoE−/− mice transplanted with AT1aR−/− or AT1aR+/+ BM. Plasma cholesterol as well as hepatic mRNA expression levels of genes involved in cholesterol metabolism were significantly lower in 2K1C mice transplanted with AT1aR−/− BM than in controls. Atherosclerotic lesions were significantly smaller in AT1aR−/− BM 2K1C mice (−79% in the aortic sinus and −71% in whole aorta compared to controls). Plaques from AT1aR−/− BM 2K1C mice exhibited reduced lipid core/fibrous cap and macrophage/smooth muscle cells ratios (−82% and −88%, respectively), and increased collagen content (+70%), indicating a more stable phenotype. Moreover, aortic mRNA levels of pro-inflammatory cytokines IL-12p35, IL-1β, and TNF-α were significantly reduced in AT1aR−/− BM 2K1C mice. No significant differences in either the number of circulating Ly6Chigh inflammatory monocytes and Ly6Clow resident anti-inflammatory monocyte subsets, or in mRNA levels of aortic M1 or M2 macrophage markers were observed between the two groups. No significant differences were observed in splenic mRNA levels of T cell subsets (Th1, Th2, Th17 and Treg) markers between the two groups. In conclusion, direct AT1R activation by Ang II on BM-derived cells promotes hepatic mRNA expression of cholesterol-metabolism-related genes and vascular mRNA expression of pro-inflammatory cytokines that may lead to plaque instability.

Abstract 5: Disruption of Semaphorin 7A Confers Protection against the Development of Atherosclerosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Shuhong Hu ◽  
Fei Yang ◽  
Chaojun Tang ◽  
Li Zhu
Keyword(s):  
Dendritic Cells ◽  
Atherosclerotic Plaque ◽  
Aortic Root ◽  
Atherosclerotic Lesion ◽  
Blood Lipid ◽  
Lesion Size ◽  
Plaque Formation ◽  
Surface Glycoprotein ◽  
Blood Lipid Profile ◽  
Cell Surface Glycoprotein

Background: Atherosclerosis is an inflammatory disease of which both innate immunity and adaptive immunity are involved. Increasing evidence suggests that Semaphorin7A (Sema7A), a membrane-associated glycosylphosphatidylinositol (GPI)-linked cell-surface glycoprotein, plays important roles in the immune system and participates in several pathophysiological processes. Whether Sema7A participates in the progress of atherosclerosis is still unclear. Here we investigated the role of Sema7A in the development of atherosclerosis using the Sema7A-deficient mice that have been crossed with atherosclerosis-prone mice. Methods and Results: Atherosclerosis-prone ApoE-/- mice were crossed with Sema7A-/- mice to generate Sema7A-/- ApoE-/- mice and Sema7A+/+ ApoE-/- mice. After 12 weeks on high fat diet, mice were sacrificed and atherosclerotic plaque size was analyzed by en face preparation following Sudan IV Red staining. Although Sema7A deletion did not change mouse blood lipid profile, atherosclerotic lesion size in the whole aorta was decreased by 51.18% (P=00024) in Sema7A-/-ApoE-/- mice (5.01±1.04%, n=13) compared to Sema7A+/+ApoE-/- control mice (10.26±1.15%, n=13). When the aortic root was analyzed using Oil Red O staining, plaque formation was reduced by 45.96% (P=0.0016) in Sema7A-/-ApoE-/- mice (15.80±2.78%, n=7) compared to Sema7A+/+ApoE-/- control mice (31.09±2.56%, n=7). Immunohistochemical studies showed that macrophages within aortic root plaques were significantly reduced by 58.437% (P=0.0010) in ApoE-/- Sema7A-/- mice (24.68±2.767%, n=14) compared with Sema7A+/+ApoE-/- control mice (59.38±4.273%, n=14). Further studies showed a significant decrease in CD4+ cells by 51.31% (P<0.0001) and dendritic cells by 60.4% (P<0.0001), respectively, in the aortic roots in ApoE-/- Sema7A-/- mice compared to ApoE-/- mice. Additionally, Sema7A-/-ApoE-/- mice showed significantly higher collagen content (P<0.0022) and vulnerability index (P <0.0001) than Sema7A+/+ApoE-/- mice. Conclusion: These results demonstrate that genetic deletion of Sema7A delayed the formation of atherosclerotic plaque formation, likely by impairment of the accumulation of macrophages, T cells and dendritic cells in vascular wall.

Abstract 1143: Imaging of Vasa Vasorum in Atherosclerotic Plaque with 99m Tc-labeled single chain-VEGF

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoru Ohshima ◽  
Shinichiro Fujimoto ◽  
Sotirios Tsimikas ◽  
Frank D Kolodgie ◽  
Renu Virmani ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Ex Vivo ◽  
Imaging Modality ◽  
Atherosclerotic Lesion ◽  
Vasa Vasorum ◽  
Intraplaque Hemorrhage ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Single Chain

Introduction: Adventitial vasa vasorum proliferation and neointimal neovascularization are associated with intraplaque hemorrhage, expansion of necrotic core and hence plaque vulnerability. Increased expression of VEGF and its receptors accompany neoangiogenic process. We used 99m Tc -labeled single chain VEGF (TcV) for developing potentially noninvasive imaging modality in experimentally induced aortic atherosclerotic lesion. Methods : Noninva-sive radionuclide imaging was performed with TcV (6.85 ±0. 27 mCi) in 6 NZW rabbits receiving high cholesterol diet (0.2% cholesterol, 4% fat) for one year and compared with 3 control rabbits receiving normal rabbit chow. Four hours after intravenous administration of TcV, micro SPECT/microCT imaging was performed for in vivo localization of tracer activity. Aortas were then explanted, and gamma counted for determination of % injected dose per gram (%ID/g). The aortas were then submitted for histopathologic characterization. Results : The uptake in thoracic aorta was clearly visualized non-invasively by TcV in vivo imaging in 4 of 5 rabbits in hypercholesterolemic rabbits, but not in the control animals. The %ID/g of each parts of aorta in hypercholesterolemic rabbits (Arch : 0.036 ± 0.020 %, Thoracic : 0.026 ± 0.012 %, Abd : 0.019 ± 0.009 %) was about 2.5-fold higher than that in control group (Arch : 0.014 ± 0.004 %, Thoracic : 0.009 ± 0.003 %, Abd : 0.009 ± 0.003 %) (figure a ). Ex vivo images of each group are shown as figure b . Conclusions : This preliminary study suggests a potentially novel strategy for non-invasive imaging of neoangiogenesis in atherosclerotic plaque and may allow identification of unstable plaques.

scholarly journals Neutrophils promote atherosclerotic plaque destabilization in a mouse model of endotoxinaemia

2018 ◽  
Vol 114 (12) ◽  
pp. 1573-1574
Author(s):  
Clément Cochain ◽  
Hafid Ait-Oufella ◽  
Alma Zernecke
Keyword(s):  
Mouse Model ◽  
Atherosclerotic Plaque ◽  
Plaque Destabilization

scholarly journals Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr−/− mice

2011 ◽  
Vol 71 (3) ◽  
pp. 408-414 ◽  
Author(s):  
Sander I van Leuven ◽  
Yanice V Mendez-Fernandez ◽  
Ashley J Wilhelm ◽  
Nekeithia S Wade ◽  
Curtis L Gabriel ◽  
...  
Keyword(s):  
T Cells ◽  
Mycophenolate Mofetil ◽  
Lupus Erythematosus ◽  
Atherosclerotic Lesion ◽  
Interleukin 10 ◽  
Lesion Size ◽  
Atherosclerotic Burden ◽  
Cholesterol Levels ◽  
Increased Risk ◽  
Dsdna Antibody

RationaleRecent clinical and preclinical studies have demonstrated that systemic lupus erythematosus (SLE) is associated with an increased risk for cardiovascular disease (CVD). However, unlike in the general population, little is known regarding the efficacy of atheroprotective interventions in patients with SLE. The current study aims to determine the benefit of lymphocyte inhibition on reducing the atherosclerotic burden in SLE-susceptible LDLr-deficient mice.MethodsFemale LDLr−/− mice were lethally irradiated and reconstituted with bone marrow from C57Bl/6 mice (LDLr.B6) or the SLE-susceptible B6.Sle1.2.3 mice (LDLr.Sle). At 16 weeks post transplant, mice were treated with atorvastatin (10 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or both (MMF-A) for 8 weeks, after which the extent of atherosclerosis and the presence of SLE were assessed.ResultsFollowing 8 weeks of treatment, we observed that atorvastatin-mediated reduction in cholesterol levels attenuated atherogenesis in LDLr.B6 mice but failed to significantly reduce atherosclerotic lesion size in LDLr.Sle mice, in spite of a significant reduction in serum cholesterol levels. Treatment with MMF and MMF-A attenuated atherogenesis in LDLr.B6 and LDLr.Sle mice. In addition, MMF-containing regimens inhibited recruitment of CD4+ T cells to atherosclerotic lesions in LDLr.Sle mice. In these mice, MMF also reduced the proportion of activated splenic T cells, as well as interleukin 10 secretion by T cells. With regard to lupus activity, MMF had no overt effect on anti-double-stranded DNA (dsDNA) antibody titres or kidney function and pathology.ConclusionsThe current study demonstrates that reduction of cholesterol levels alone is not atheroprotective in lupus-mediated atherogenesis. This is the first study to demonstrate that MMF reduces the atherosclerotic burden in a model of lupus-accelerated atherosclerosis. Our results suggest that MMF treatment may prove beneficial in preventing CVD in patients with SLE.

scholarly journals Consumption of Non-Nutritive Sweetener, Acesulfame Potassium Exacerbates Atherosclerosis through Dysregulation of Lipid Metabolism in ApoE−/− Mice

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3984
Author(s):  
Cheng-Hsin Lin ◽  
Hung-Yuan Li ◽  
Shu-Huei Wang ◽  
Yue-Hwa Chen ◽  
Yang-Ching Chen ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Lipid Metabolism ◽  
Atherosclerotic Plaque ◽  
Atherosclerotic Lesion ◽  
Plasma Lipid ◽  
High Cholesterol Diet ◽  
Hepatic Lipogenesis ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Raw264.7 Macrophages

Obesity is associated with the risk of cardiovascular disease, and non-nutritive sweetener, such as acesulfame potassium (AceK) has been used to combat obesity. However, the effects of AceK on cardiovascular disease are still unclear. In this study, high cholesterol diet (HCD)-fed ApoE−/− mice had dysregulated plasma lipid profile, and developed atherosclerosis, determined by atherosclerotic plaque in the aorta. Supplement of AceK in HCD worsened the dyslipidemia and increased atherosclerotic plaque, as compared with HCD-fed ApoE−/− mice. Since treatment of AceK in RAW264.7 macrophages showed no significant effects on inflammatory cytokine expressions, we then investigated the impacts of AceK on lipid metabolism. We found that AceK consumption enhanced hepatic lipogenesis and decreased β-oxidation in ApoE−/− mice. In addition, AceK directly increased lipogenesis and decreased β-oxidation in HepG2 cells. Taken together, a concurrent consumption of AceK exacerbated HCD-induced dyslipidemia and atherosclerotic lesion in ApoE−/− mice, and AceK might increase the risk of atherosclerosis under HCD.

Abstract 289: Chronic Systemic Insulin Treatment Attenuates Atherosclerotic Lesion Development in Cholesterol-Fed ApoE -/- Mice.

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Simon Chiang ◽  
Joanne Britto ◽  
Adria Giacca
Keyword(s):  
Atherosclerotic Plaque ◽  
Atherosclerotic Lesion ◽  
High Cholesterol Diet ◽  
Descending Aorta ◽  
Increased Risk ◽  
Significant Difference ◽  
En Face ◽  
Pre Treatment ◽  
Oil Red O Staining ◽  
Oil Red O

Diabetes mellitus and metabolic syndrome, which are states of insulin resistance, are both well-known to increase the risk of atherosclerosis. However, it is still debated whether this increased risk is due to excess or lack of insulin action. Here, we present evidence that insulin is anti-atherogenic and decreases atherosclerosis independent of its effects on glycemia. ApoE -/- mice were fed a 1.25% (w/w) high cholesterol diet for 1 week pre-treatment then implanted with either control pellets or insulin pellets (0.05U/day which achieves a mild 4-fold elevation of circulating insulin without significantly lowering plasma glucose) subcutaneously for 12 weeks thereafter. At the end of the treatment, the mice were perfused and the aortas were harvested. Using en face Oil-Red O staining, the atherosclerotic plaque in the descending aorta was evaluated by measuring lesion area over total area. Insulin-treated mice (n=7) showed a significant decrease in atherosclerotic plaque (9.0 ± 2%) compared to control (n=11; 17.6 ± 2.5%). There was no significant difference in glycemia between the two groups. Based on our results, insulin is anti-atherogenic in the context of euglycemia.

Tanshinone IIA Promotes Macrophage Cholesterol Efflux and Attenuates Atherosclerosis of apoE-/- Mice by Omentin-1/ABCA1 Pathway

2019 ◽  
Vol 20 (5) ◽  
pp. 422-432 ◽  
Author(s):  
Yu-lin Tan ◽  
Han-xiao Ou ◽  
Min Zhang ◽  
Duo Gong ◽  
Zhen-wang Zhao ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Lipid Content ◽  
Plasma Levels ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Tanshinone Iia ◽  
Lipoprotein Cholesterol ◽  
Mrna Levels ◽  
Cellular Lipid ◽  
Oil Red O

Background: Tanshinone IIA (Tan IIA) and Omentin-1 have a protective role in the cardiovascular system. However, if and how Tan IIA and Omentin-1 regulate cholesterol metabolism in macrophages has not been fully elucidated. Objective: To investigate the possible mechanisms of Tan IIA and Omentin-1 on preventing macrophage cholesterol accumulation and atherosclerosis development. Methods: The effect of Tan IIA on the protein and mRNA levels of Omentin-1 and ATP-binding cassette transporter A1 (ABCA1) in macrophages was examined by Western blot and qRT-PCR assay, respectively. Cholesterol efflux was assessed by liquid scintillation counting (LSC). Cellular lipid droplet was measured by Oil Red O staining, and intracellular lipid content was detected by high performance liquid chromatography (HPLC). In addition, the serum lipid profile of apoE−/− mice was measured by enzymatic method. The size of atherosclerotic lesion areas and content of lipids and collagen in the aortic of apoE−/− mice were examined by Sudan IV, Oil-red O, and Masson staining, respectively. Results: Tan IIA up-regulated expression of Omentin-1 and ABCA1 in THP-1 macrophages, promoting ABCA1-mediated cholesterol efflux and consequently decreasing cellular lipid content. Consistently, Tan IIA increased reverse cholesterol transport in apoE−/− mice. Plasma levels of high-density lipoprotein cholesterol (HDL-C), ABCA1 expression and atherosclerotic plaque collagen content were increased while plasma levels of low-density lipoprotein cholesterol (LDL-C) and atherosclerotic plaque sizes were reduced in Tan IIA-treated apoE−/− mice. These beneficial effects were, however, essentially blocked by knockdown of Omentin-1. Conclusion: Our results revealed that Tan IIA promotes cholesterol efflux and ameliorates lipid accumulation in macrophages most likely via the Omentin-1/ABCA1 pathway, reducing the development of aortic atherosclerosis.

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