Abstract 344: Bcl-x Inactivation in Macrophages Accelerates Progression of Advanced Atherosclerotic Lesions in Apoe -/- Mice

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Philippe Lesnik ◽  
Virginie Deswaerte ◽  
Emmanuel L Gautier ◽  
Flora Saint-Charles ◽  
John Pirault ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Cholesterol Metabolism ◽  
Apoptotic Cell ◽  
Atherosclerotic Lesion ◽  
The Body ◽  
Plaque Progression ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels ◽  
Macrophage Apoptosis

Background: Bcl-x is the most abundantly expressed member of the Bcl-2 gene family in macrophages but its role in macrophage apoptosis during atherogenesis is unknown. Methods and results: We previously reported dual pro- and anti-atherogenic effects of macrophage survival in early versus advanced atherosclerotic lesions respectively, potentially reflecting growing impairment of efferocytosis during plaque progression. Here, we specifically inactivated Bcl-x in macrophages and evaluated its impact on atherosclerotic lesion formation in Apoe -/- mice at various stages of the disease. Bcl-x deficiency in macrophages increased susceptibility to apoptosis, resulting in the depletion of tissue macrophages in vivo, including its major pool, Küppfer cells in the liver. We also observed increased cholesterol levels, that was however not associated with any acceleration of early atherosclerotic plaque progression. This observation, suggests that the atheroprotective effect of macrophage apoptosis at that stage of disease was counterbalanced by enhanced cholesterol levels. Bcl-x KOmac/Apoe -/- mice exhibited significantly larger advanced lesions than control mice. These lesions showed vulnerable traits. Such enhanced lesion size may occur as a result not only of apoptotic cell accumulation but also of elevated cholesterol levels. Conclusions: Modulation of macrophage resistance to apoptosis through targeted deletion of Bcl-x has a major impact on the entire macrophage cell population in the body, including Küpffer cells. Macrophage survival may, therefore, not only influence atherosclerotic plaque development and vulnerability but also cholesterol metabolism.

Prostate cancer-derived anti-GRP78 autoantibodies compromise the blood-brain barrier and accelerate atherosclerosis progression in vivo.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 205-205
Author(s):  
Ali Al-Hashimi ◽  
Bobby Shayegan ◽  
Richard Austin ◽  
Kevin Doyoon Won
Keyword(s):  
Prostate Cancer ◽  
Blood Brain Barrier ◽  
Atherosclerotic Plaque ◽  
The Body ◽  
Brain Barrier ◽  
Blue Dye ◽  
Plaque Progression ◽  
Blood Brain

205 Background: Pathological conditions of prostate cancer (PCa) drive the translocation of the endoplasmic reticulum-resident chaperone, GRP78, to the cell surface (cs) where it acts as an antigenic protein with signaling properties. In PCa, csGRP78 drives the production of anti-GRP78 autoantibodies (AutoAbs) that engage csGRP78 and promote PCa survival/progression. New studies now demonstrate csGRP78 expression on endothelial cells (EC) that line the arterial vasculature and the blood-brain barrier (BBB) suggesting that these AutoAbs can affect other systems in the body. Based on this, we investigated how the engagement of anti-GRP78 AutoAbs to csGRP78 on EC can contribute to EC-dysfunction that can promote atherosclerosis and compromise the integrity of the BBB. Methods: Anti-GRP78 AutoAbs were purified from PCa patients (St. Joseph’s Healthcare Hamilton); human aortic EC and the ApoE -/- mouse model were used for in vitro and in vivo investigations, respectively. EC or mice were treated with anti-GRP78 AutoAbs or IgG control (60µg/mL); EC-dysfunction was investigated by measuring attachment protein expression, in vitro. In vivo evaluation was carried out by studying atherosclerotic plaque progression (immunohistochemistry; aorta); the BBB integrity was examined using the Evans Blue dye. Results: Mice injected with anti-GRP78 AutoAbs, and not human IgG, demonstrated larger atherosclerotic plaque volume and hallmarks of a leaky BBB. In terms of a mechanism, in vitro studies demonstrated that treating EC with anti-GRP78 AutoAbs resulted in activation of the NFκB pathway that led to increased expression of attachment proteins. All these effects were reversed by using a recombinant molecule that interfere with the binding of the AutoAb to csGRP78. Conclusions: We have identified anti-GRP78 AutoAb as a driver of EC-dysfunction that promote atherosclerotic plaque progression and damage to the BBB. Our results indicate that interfering with anti-GRP78 AutoAb:csGRP78 complex can reverse the pathological effects of the AutoAbs. This novel data suggests that patient-derived anti-GRP78 autoantibodies systemically drive pathologies, other than cancer, in vivo.

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.

Abstract 445: Increasing Macrophage Survival Delays Progression of Advanced Atherosclerotic Lesions Through Macrophage-Derived ApoE

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Laura Bouchareychas ◽  
John Pirault ◽  
Flora Saint Charles ◽  
Virginie Deswaerte ◽  
Philippe Giral ◽  
...  
Keyword(s):  
Kupffer Cells ◽  
Bone Marrow Cells ◽  
Therapeutic Potential ◽  
Plasma Cholesterol ◽  
Cholesterol Homeostasis ◽  
Mrna Levels ◽  
Plaque Progression ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels

Introduction/Hypothesis: We previously demonstrated that increasing macrophage survival delayed atherosclerotic plaque progression towards advanced stages. However, whether cell death-protected macrophages would still be efficient to hinder the progression and favor the resolution of already advanced atherosclerotic lesions, and thus prove therapeutic potential, remains unknown. Methods: We used a transgenic mouse model in which macrophage lifespan is enhanced through specific overexpression of the antiapoptotic gene hBcl-2 under the control of the macrophage specific CD68 promoter (Mø-hBcl2). Apoe -/- or Ldlr -/- recipient mice with advanced atherosclerotic lesions were irradiated and then transplanted with bone marrow cells isolated from Apo e -/- Mø-h Bcl2 or Apo e +/+ Mø-hBcl2 mice respectively and their appropriate controls. Results: Both Apoe -/- Mø-h Bcl2 → Apoe -/- and Apoe +/+ Mø-h Bcl2 → Ldl r -/- mice presented a significant decrease in lesional apoptotic cells content (-30%, P<0.05) as compared to their respective controls. Additionally, hBcl2 expression in macrophages was associated with a larger pool of tissue macrophages in vivo, including Küppfer cells in the liver, in both Apoe -/- (+40% P<0.05) and Ldlr -/- (+36% P<0.05) recipients. By contrast, only Ldlr -/- recipient mice showed reduction of lesional necrotic areas (-37%, P<0.05), plasma cholesterol levels (-15%, P<0.05) and atherosclerotic lesions (-30%, P<0.05). As those reductions were not significant in the context of ApoE deficiency, these findings supported that Mø-derived ApoE was key in regulating plasma cholesterol levels, lesional necrosis and advanced plaque progression in the context of increased macrophage pool. Indeed, increased liver Küpffer cells content in the liver of Ldlr -/- recipient mice was associated with elevated ApoE mRNA levels (+30%, P<0.05), which is likely to promote reverse cholesterol transport. Conclusions: Collectively, these data suggest that macrophage survival hindered advanced lesion progression. One potential mechanistic explanation lied to the increased Küpffer cells content, which could modulate directly or indirectly cholesterol homeostasis.

scholarly journals Hydroxytyrosol Plays Antiatherosclerotic Effects through Regulating Lipid Metabolism via Inhibiting the p38 Signal Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xinxin Zhang ◽  
Yating Qin ◽  
Xiaoning Wan ◽  
Hao Liu ◽  
Chao Iv ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Fold Increase ◽  
Heart Tissue ◽  
Control Group ◽  
Atherosclerotic Lesions ◽  
Serum Crp

Purpose. Hydroxytyrosol (HT) processes multiaspect pharmacological properties such as antithrombosis and antidiabetes. The aim of this study was to explore the antistherosclerotic roles and relevant mechanisms of HT. Methods. Male apoE-/- mice were randomly divided into 2 groups: the control group and the HT group (10 mg/kg/day orally). After 16 weeks, blood tissue, heart tissue, and liver tissue were obtained to detect the atherosclerotic lesions, histological analysis, lipid parameters, and inflammation. And the underlying molecular mechanisms of HT were also studied in vivo and in vitro. Results. HT administration significantly reduced the extent of atherosclerotic lesions in the aorta of apoE-/- mice. We found that HT markedly lowered the levels of serum TG, TC, and LDL-C approximately by 17.4% (p=0.004), 15.2% (p=0.003), and 17.9% (p=0.009), respectively, as well as hepatic TG and TC by 15.0% (p<0.001) and 12.3% (p=0.003), respectively, while inducing a 26.9% (p=0.033) increase in serum HDL-C. Besides, HT improved hepatic steatosis and lipid deposition. Then, we discovered that HT could regulate the signal flow of AMPK/SREBP2 and increase the expression of ABCA1, apoAI, and SRBI. In addition, HT reduced the levels of serum CRP, TNF-α, IL-1β, and IL-6 approximately by 23.5% (p<0.001), 27.8% (p<0.001), 18.4% (p<0.001), and 19.1% (p<0.001), respectively, and induced a 1.4-fold increase in IL-10 level (p=0.014). Further, we found that HT might regulate cholesterol metabolism via decreasing phosphorylation of p38, followed by activation of AMPK and inactivation of NF-κB, which in turn triggered the blockade of SREBP2/PCSK9 and upregulation of LDLR, apoAI, and ABCA1, finally leading to a reduction of LDL-C and increase of HDL-C in the circulation. Conclusion. Our results provide the first evidence that HT displays antiatherosclerotic actions via mediating lipid metabolism-related pathways through regulating the activities of inflammatory signaling molecules.

Human Carotid Atherosclerotic Plaque Growth Function and Progression Simulation Using Meshless GFD and Statistical Methods Based on Multi-Year In Vivo MRI

2008 ◽  
Author(s):  
Chun Yang ◽  
Joseph D. Petruccelli ◽  
Zhongzhao Teng ◽  
Chun Yuan ◽  
Gador Canton ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Wall Thickness ◽  
Vessel Wall ◽  
Plaque Rupture ◽  
Patient Specific ◽  
Tracking Data ◽  
Plaque Progression ◽  
Vessel Wall Thickness ◽  
Plaque Growth

Atherosclerotic plaque rupture and progression have been the focus of intensive investigations in recent years. The mechanisms governing plaque progression and rupture process are not well understood. Using computational models based on patient-specific multi-year in vivo MRI data, our recent results indicated that 18 out of 21 patients studied showed significant negative correlation between plaque progression measured by vessel wall thickness increase (WTI) and plaque wall (structural) stress (PWS) [1]. In this paper, a computational procedure based on meshless generalized finite difference (MGFD) method and serial magnetic resonance imaging (MRI) data was introduced to simulate plaque progression. Participating patients were scanned three times (T1, T2, and T3, at intervals of approximately 18 months) to obtain plaque progression data. Vessel wall thickness (WT) changes were used as the measure for plaque progression. Starting from T2 plaque geometry, plaque progression was simulated by solving the solid model and adjusting wall thickness using plaque growth functions iteratively until time T3 is reached. Numerically simulated plaque progression showed very good agreement with actual plaque geometry at T3 given by MRI data. We believe this is the first time plaque progression simulation results based on multi-year patient-tracking data are reported. Multi-year tracking data and MRI-based progression simulation add time dimension to plaque vulnerability assessment and will improve prediction accuracy.

scholarly journals Detection of in vivo atherosclerotic plaque progression with a fibrin-targeted MR contrast agent

2010 ◽  
Vol 12 (Suppl 1) ◽  
pp. O55
Author(s):  
Marcus R Makowski ◽  
Sarah Forbes ◽  
Ulrike Blume ◽  
René M Botnar ◽  
Andrea J Wiethoff
Keyword(s):  
Contrast Agent ◽  
Atherosclerotic Plaque ◽  
Plaque Progression

Rapid stabilisation of atherosclerotic plaque with 5-aminolevulinic acid-mediated sonodynamic therapy

2015 ◽  
Vol 114 (10) ◽  
pp. 793-803 ◽  
Author(s):  
Liping Wang ◽  
Tengyu Wang ◽  
Chenghai Peng ◽  
Wei Wang ◽  
Zhen Tian ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Atherosclerotic Plaque ◽  
Aminolevulinic Acid ◽  
Apoptotic Cell ◽  
Tube Placement ◽  
Sonodynamic Therapy ◽  
Percentage Content ◽  
Plaque Disruption ◽  
Plaque Stabilisation

Summary5-Aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) effectively induces the apoptosis of atherogenic macrophages, but whether it can stabilise atherosclerotic plaque in vivo is unclear. Here, we used an animal model to evaluate the effects of ALA-SDT on plaque stabilisation. Sixty rabbits were induced atherosclerotic plaques in the femoral artery with a combination of silastic tube placement with atherogenic diet, and randomly assigned into control (n = 12) and SDT (n = 48) groups. In the SDT group, after intravenous injected with ALA (60 mg/kg) animals underwent the treatment of ultrasound with intensities of 0.75, 1.00, 1.50 and 2.00 W/cm2 (n = 12 for each intensity). Seven days after the treatment, the plaque disruption assay was performed to test plaque stability. We found that ALA-SDT with ultrasound intensity of 1.5 W/cm2 showed the strongest efficacy to stabilise plaques. Under this condition, the frequency of plaque disruption decreased by 88 % (p < 0.01), positive area of macrophages reduced by 94 % (p < 0.001) and percentage content of lipids dropped by 60 % (p < 0.001), while percentage content of collagens increased by 127 % (p < 0.001). We also found that the plaque stabilisation by ALA-SDT was associated with increased macrophage apoptosis and apoptotic cell clearance. Moreover, ALA-SDT decreased the contents and activities of matrix metalloproteinase-2,9 and increased the levels of tissue inhibitors of matrix metalloproteinase-1,2 in plaques. Our studies demonstrate that ALA-SDT promotes plaque stabilisation by inducing macrophage elimination and inhibiting matrix degradation. This method might be a promising regimen for atherosclerosis therapy.

Cellular Cholesterol Modulates VEGFR-1 Function on Acute Leukemia Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1847-1847
Author(s):  
Rita Fragoso ◽  
Cristina Casalou ◽  
Sergio Dias
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Acute Leukemia ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Leukemia Cell ◽  
Protein Translation ◽  
Leukemia Cells ◽  
Cholesterol Levels

Abstract Vascular endothelial growth factor (VEGF) and its receptors play a crucial role in malignancy and in disease, regulating the survival, proliferation, and migration of several cell types, such as endothelium and also leukemia cells. Following our recent report on the role of VEGFR-1 (FLT-1) in ALL (Fragoso R et al, 2006), in the present study we analyzed the molecular mechanisms whereby it modulates acute leukemia cell migration in response to VEGF/Placental Growth Factor (PLGF). First, we observed the formation of cell protrusions on ALL cells after VEGF/PLGF stimulation, with evidence for polymerized actin and FLT-1 co-localization (as determined by phalloidin, immunofluorescence staining, and confocal microscopy). Western blot analysis revealed that PLGF/VEGF stimulation resulted in increased RhoA and Rac1 GTPases expression. Co-treatment with LY200942 significantly decreased RhoA and Rac1 induction and cell migration by PLGF/VEGF, demonstrating this effect is modulated via Pi3 kinase. Next, we investigated the mechanisms whereby FLT-1 and actin co-localize at the cell “leading edge” (protrusions), after VEGF/PLGF stimulation, and the relevance of such co-localization for cell migration. We addressed this question by impairing the formation of lipid rafts/caveolae using drugs that either sequester (nystatin) or deplete (methyl-β-ciclodextrin) total cholesterol. Accordingly, co-treatment of leukemia cells with nystatin or MβCD and PLGF/VEGF blocked cell migration, an effect that was associated with a decrease in FLT-1 polarization and co-localization with actin filaments. Instead, FLT-1 was now found mostly in the cell cytosol. Given that leukemia cells have an increased rate of cholesterol up-take we sought to understand if increased cholesterol levels affected FLT-1 function in leukemia cells. Cholesterol repletion in leukemia cells enhanced leukemia cells migration in response to VEGF/PlGF (about 3 folds). This significant increase was associated with an increase in FLT-1 protein expression that, very interestingly, was particularly concentrated intracellulary in the cytoplasm. At this time we are trying to understand if this increase in FLT-1 expression after cholesterol repletion is associated with increase protein translation or impairment in proteasome activity. Finally, our preliminary in vivo experiments using Nod-Scid mice subjected (n=3) or not (n=3) to high fat diet (that results in increased cholesterol levels in the BM and in the spleen), showed this metabolic condition worsens disease symptoms and significantly decreases mouse survival. These results reveal for the first time some of the molecular mechanisms involved in FLT-1-mediated leukemia migration, namely the involvement of cholesterol metabolism, which may be crucial for new therapeutics delineation.

Elimination of Platelet Factor 4 (PF4) from Platelets Reduces Atherosclerosis and Increases HDL Cholesterol in C57Bl/6 and ApoE−/− Mice.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 418-418
Author(s):  
Bruce S. Sachais ◽  
Tiffany Turrentine ◽  
Jeanine M. Dawicki-McKenna ◽  
Daniel J. Rader ◽  
M. Anna Kowalska
Keyword(s):  
Atherosclerotic Lesion ◽  
Annexin V ◽  
Hdl Cholesterol ◽  
Fold Increase ◽  
Platelet Factor 4 ◽  
Spontaneous Bleeding ◽  
Platelet Factor ◽  
Cholesterol Levels ◽  
Fold Reduction

Abstract There is a presence of circulating, activated platelets in blood of patients with atherosclerosis, coronary disease and hypercholesterolemia. Upon activation, platelets release a large amount of platelet factor 4 (PF4), a platelet specific chemokine. Our laboratory has previously demonstrated several potentially proatherogenic properties of PF4 including alteration of LDL metabolism and cellular trafficking, and activation of NFkB, a proinflammatory transcription factor involved in atherosclerosis. We have also localized PF4 to human atherosclerotic lesions. However, to date, no direct in vivo evidence for the involvement of PF4 in atherogenesis. In the current study, we have bred PF4−/− mice onto two athero-susceptible backgrounds, WT-C57Bl/6(WT) and apoE−/−, to examine the importance of PF4 in atherogenesis. PF4−/− and PF4−/−apoE−/− (DKO) mice are viable and healthy, with no spontaneous bleeding disorders. In order to induce atherosclerosis, WT and PF4−/− mice were fed an atherogenic Paigen diet for 30 weeks (Study 1), while apoE−/− and DKO mice were fed a high fat Western style diet for 10 weeks (Study 2). Examination of lesions in the aortic roots of Study 1 animals demonstrated a 5-fold reduction in PF4−/− compared to WT mice (p = 0.008). Measurement of cholesterol levels demonstrated similar total and non-HDL cholesterol levels in WT and PF4−/− mice. However, HDL cholesterol was significantly increased in PF4−/− mice compared to WT (2.5-fold, p = 0.001). Examination of apoE−/− mice (Study 2) demonstrated similar changes, with DKO mice demonstrating a 2.7-fold reduction in aortic atherosclerosis (measured by the en face method; p = 0.03) and a 1.7-fold increase in HDL cholesterol (p = 0.02) compared to apoE−/− mice. Although platelet counts were increased by ~30% in mice lacking PF4, the activation state of the platelets in our mice at sacrifice (WT vs PF4−/− and apoE−/− vs DKO) were similar as measured by both p-selectin expression and annexin V binding. These data demonstrate, for the first time, that the platelet specific chemokine PF4 promotes atherosclerotic lesion development in vivo.

scholarly journals Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

2017 ◽  
Vol 114 (13) ◽  
pp. E2766-E2775 ◽  
Author(s):  
Yaw Asare ◽  
Miriam Ommer ◽  
Florence. A. Azombo ◽  
Setareh Alampour-Rajabi ◽  
Marieke Sternkopf ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Cop9 Signalosome ◽  
Macrophage Phenotype ◽  
Ring E3 Ligase ◽  
Atherosclerotic Lesions ◽  
Arginase 1 ◽  
Proinflammatory Gene ◽  
A Subunit

Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell-expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed “deNEDDylase”) and a subunit of the cullin-RING E3 ligase-regulating COP9 signalosome complex, attenuates proinflammatory NF-κB signaling. We previously showed that CSN5 is up-regulated in human atherosclerotic arteries. Here, we investigated the role of CSN5 in atherogenesis in vivo by using mice with myeloid-specific Csn5 deletion. Genetic deletion of Csn5 in Apoe−/− mice markedly exacerbated atherosclerotic lesion formation. This was broadly observed in aortic root, arch, and total aorta of male mice, whereas the effect was less pronounced and site-specific in females. Mechanistically, Csn5 KO potentiated NF-κB signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1α levels were reduced. Inversely, inhibition of NEDDylation by MLN4924 blocked proinflammatory gene expression and NF-κB activation while enhancing HIF-1α levels and the expression of M2 marker Arginase 1 in inflammatory-elicited macrophages. MLN4924 further attenuated the expression of chemokines and adhesion molecules in endothelial cells and reduced NF-κB activation and monocyte arrest on activated endothelium in vitro. In vivo, MLN4924 reduced LPS-induced inflammation, favored an antiinflammatory macrophage phenotype, and decreased the progression of early atherosclerotic lesions in mice. On the contrary, MLN4924 treatment increased neutrophil and monocyte counts in blood and had no net effect on the progression of more advanced lesions. Our data show that CSN5 is atheroprotective. We conclude that MLN4924 may be useful in preventing early atherogenesis, whereas selectively promoting CSN5-mediated deNEDDylation may be beneficial in all stages of atherosclerosis.

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