Abstract 662: Maternal Soy Protein Diet Ameliorates Atherosclerotic Lesions in ApoE-Deficient Mice Offspring by Promoting Anti-inflammatory Responses Through Epigenetic Changes

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Shanmugam Nagarajan ◽  
Ramona Burris ◽  
Sara Wick
Keyword(s):  
Protective Effect ◽  
Soy Protein ◽  
Inflammatory Responses ◽  
Maternal Diet ◽  
Soy Protein Isolate ◽  
Atherosclerotic Lesion ◽  
Alternative Mechanism ◽  
Aortic Sinus ◽  
Atherosclerotic Lesions ◽  
Anti Inflammatory

Maternal hypercholesterolemia has been implicated with an earlier onset of atherosclerotic lesions in neonatal offspring. In this study, we investigated whether gestational exposure to soy protein isolate (SPI) diet (maternal diet) primes the vessel wall to attenuate development of atherosclerosis in adult F1 offspring. Pregnant apolipoprotein E knockout (apoE-/-) female mice were fed SPI diet until postnatal day 21 (PND21) of the offspring (SPI-offspring). At PND21, SPI-offspring was switched to casein (CAS) diet until PND140. Mice fed CAS throughout the lifetime (gestation to adult) were used as control (CAS-offspring). Atherosclerotic lesions in aortic sinus were reduced in SPI-offspring compared with CAS-offspring. Total cholesterol levels in CAS- or SPI-offspring, and CAS- or SPI-fed dams were not different suggesting that alternative mechanism(s) contributes to the athero-protective effect of gestational SPI diet. Aortic VCAM-1, MCP-1 and TNF-α mRNA and protein expression were elevated in CAS offspring, while expression of these molecules were 50% reduced in SPI-offspring. Interestingly, compared to CAS-offspring IFN-γ expression (Th1) was reduced, while expression of IL-10 (Th2/Treg), and IL-13 (Th2) expression was increased in SPI-offspring, suggesting that Th2/Treg bias could have contributed to the athero-protective effect. DNA methylation analyses revealed gata3 and il13 promoter regions were hypomethylated in SPI-offspring. We conclude that in utero soy protein exposure inhibits susceptibility to atherosclerotic lesion formation by promoting anti-inflammatory responses through epigenetic regulation.

scholarly journals RIPK1 Expression Associates with Inflammation in Early Atherosclerosis in Humans and Can be Therapeutically Silenced to Reduce NF-κB Activation and Atherogenesis in Mice

Circulation ◽  
2020 ◽  
Author(s):  
Denuja Karunakaran ◽  
My-Anh Nguyen ◽  
Michele Geoffrion ◽  
Dianne Vreeken ◽  
Zachary Lister ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Early Stage ◽  
Oxidized Ldl ◽  
Loss Of Function ◽  
Aortic Sinus ◽  
Atherosclerotic Lesions

Background: Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. Previously, we showed that macrophages in the atherogenic plaque undergo RIPK3-MLKL-dependent programmed necroptosis in response to sterile ligands such as oxidized LDL and damage-associated patterns (DAMPs) and necroptosis is active in advanced atherosclerotic plaques. Upstream of the RIPK3-MLKL necroptotic machinery lies RIPK1, which acts as a master switch that controls whether the cell undergoes NFκB-dependent inflammation, caspase-dependent apoptosis or necroptosis in response to extracellular stimuli. We therefore set out to investigate the role of RIPK1 in the development of atherosclerosis, which is largely driven by NFκB-dependent inflammation at early stages. We hypothesize that, unlike RIPK3 and MLKL, RIPK1 primarily drives NFκB-dependent inflammation in early atherogenic lesions and knocking down RIPK1 will reduce inflammatory cell activation and protect against the progression of atherosclerosis. Methods: We examined expression of RIPK1 protein and mRNA in both human and mouse atherosclerotic lesions, and using loss-of-function approaches in vitro in macrophages and endothelial cells to measure inflammatory responses. We administered weekly injections of RIPK1 anti-sense oligonucleotides (ASO) to Apoe -/- mice fed a cholesterol-rich (Western) diet for 8 weeks. Results: We find RIPK1 expression is abundant in early-stage atherosclerotic lesions in both humans and mice. Treatment with RIPK1 ASOs led to a reduction in aortic sinus and en face lesion areas (47.2% or 58.8% decrease relative to control, p<0.01) and plasma inflammatory cytokines (IL-1α, IL-17A, p<0.05) compared to controls. RIPK1 knockdown in macrophages decreased inflammatory genes (NFκB, TNFα, IL-1α) and in vivo LPS- and atherogenic diet-induced NF-κB activation. In endothelial cells, knockdown of RIPK1 prevented NF-κB translocation to the nucleus in response to TNFα, where accordingly there was a reduction in gene expression of IL1B, E-selectin and monocyte attachment. Conclusions: We have identified RIPK1 as a central driver of inflammation in atherosclerosis by its ability to activate the NF-κB pathway and promote inflammatory cytokine release. Given the high levels of RIPK1 expression in human atherosclerotic lesions, our study suggests RIPK1 as a future therapeutic target to reduce residual inflammation in patients at high risk of coronary artery disease.

scholarly journals Protective Effect of Silibinin on Lipopolysaccharide-Induced Inflammatory Responses in Equine Peripheral Blood Mononuclear Cells, an In Vitro Study

Animals ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 2022
Author(s):  
Enrico Gugliandolo ◽  
Rosalia Crupi ◽  
Vito Biondi ◽  
Patrizia Licata ◽  
Salvatore Cuzzocrea ◽  
...  
Keyword(s):  
Protective Effect ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Mammalian Species ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Anti Inflammatory

Although inflammation is an important physiological response, it plays a prominent role in several diseases across the mammalian species. In horses, in particular, inflammation secondary to bacterial infection or translocation is one of the most frequent causes of morbidity and mortality. Research in new molecules with anti-inflammatory and immunomodulatory proprieties and safe use profile is constantly an active field; natural compounds are an important source of molecules with peculiar properties such as antioxidants, anti-inflammatory and immune modulating. Silibinin, a natural polyphenolic flavonoid, extracted from plant milk thistle, Silybum marianum, has been reported to have actions such as antioxidant immunomodulatory and anti-inflammatory. The aim of this study was to test the effect of silibinin on lipopolysaccharide (LPS)-induced inflammatory response in equine peripheral blood mononuclear cells (PBMCs). Our results showed the protective effect of silibinin 10 μM and 50 μM in equine PBMCs stimulated with LPS. Silibilinin was able to prevent the LPS induced increased levels of TNF-α, IL-1β, IL-6 and IL-8. The results from this study on LPS-stimulated equine PBMCs showed that silibinin could be a useful pharmacological approach in treatment or prevention of several inflammatory conditions in horse.

scholarly journals Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Yuri V. Bobryshev ◽  
Ekaterina A. Ivanova ◽  
Dimitry A. Chistiakov ◽  
Nikita G. Nikiforov ◽  
Alexander N. Orekhov
Keyword(s):  
Inflammatory Responses ◽  
Current Knowledge ◽  
Atherosclerotic Lesions ◽  
Plaque Stabilization ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Unstable Plaques ◽  
Comprehensive Classification ◽  
Cellular Tests ◽  
Inflammatory Macrophages

Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage-based cellular tests for evaluation of potential antiatherosclerotic substances.

Abstract 068: Endothelin-1 Exaggerates Type-1 Diabetes-accelerated Atherosclerosis Through NADPH Oxidases 1 and 4

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sofiane Ouerd ◽  
Noureddine Idris-Khodja ◽  
Michelle Trindade ◽  
Suellen C Coelho ◽  
Mario F Neves ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Plasma Cholesterol ◽  
Vascular Complications ◽  
Atherosclerotic Lesion ◽  
Fold Increase ◽  
Mesenteric Arteries ◽  
Aortic Sinus ◽  
Accelerated Atherosclerosis ◽  
Plaque Area ◽  
Atherosclerotic Lesions

Objective: NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout ( Apoe -/- ) mice exaggerated high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We hypothesized that ET-1 overexpression in the endothelium would exaggerate diabetes-accelerated atherosclerosis through a mechanism involving NOX1 but not NOX4. Methods: Six-week-old male Apoe -/- mice, eET-1/ Apoe -/- and eET-1/ Apoe -/- mice deficient in Nox1 (eET-1/ Apoe -/- / Nox1 y/- ) or Nox4 (eET-1/ Apoe -/- / Nox4 -/- ) were rendered diabetic with 55 mg/kg/day streptozotocin (STZ) IP injections for 5 days and studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Aortic atherosclerotic lesions were quantified using Oil Red O staining. Plasma cholesterol, HDL and triglycerides were measured. Results: Diabetic Apoe -/- mice presented an impaired endothelium-dependent vasodilatory response to acetylcholine, which was not observed in diabetic eET-1/ Apoe -/- , eET-1/ Apoe -/- / Nox1 y/- or eET-1/ Apoe -/- / Nox4 -/- mice (E max : 20±6 vs 99±1, 98±1 and 100±0%). ET-1 overexpression caused a 1.8-fold increase in MA media/lumen of diabetic Apoe -/- mice (5.3±0.3 vs 2.9±0.2%), which was further increased 1.2-fold by Nox4 (6.4±0.3%) but not Nox1 knockout (5.5±0.3%). ET-1 overexpression exaggerated >2-fold the atherosclerotic lesion area in the aortic sinus in diabetic Apoe -/- mice (plaque area [x10 5 μm 2 ]: 5.3±0.5 vs 2.9±0.6), which was reduced ~40% by Nox1 and Nox4 knockout (plaque area [x10 5 μm 2 ]: 3.3±0.6 and 3.6±0.6). Plasma triglycerides were unaffected by ET-1 overexpression but reduced by Nox1 (2.2±0.4 vs 3.4±0.3 mmol/L) and Nox4 knockout (1.8±0.4 mmol/L). Plasma HDL and cholesterol were similar between groups. Conclusions: Increased levels of ET-1 exaggerate diabetes-accelerated atherosclerosis through NOX1 and NOX4, despite paradoxically improving endothelium-dependent relaxation in small arteries.

Fibronectin Isoform Containing the Alternatively-Spliced Extra Domain A in Circulation Accelerates the Development of Atherosclerosis in Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2205-2205
Author(s):  
Chintan Gandhi ◽  
Mohammad Moshahid Khan ◽  
Anil K Chauhan
Keyword(s):  
Atherosclerotic Plaque ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Atherosclerotic Lesion ◽  
Plaque Formation ◽  
Western Diet ◽  
High Fat ◽  
Aortic Sinus ◽  
Atherosclerotic Plaque Formation ◽  
Alternatively Spliced

Abstract Abstract 2205 Background and Objective: The fibronectin isoform containing the alternatively-spliced extra domain A (EDA+-FN) is normally absent from the circulation, but plasma levels of EDA+-FN can become markedly elevated in several pathological conditions including atherosclerosis. It remains unclear in humans whether these elevated levels of EDA+-FN are actively contributing to disease pathogenesis, or rather simply serving as a marker associated with vascular stress and/or injury. Several in vitro studies suggest that EDA+-FN can activate toll-like receptor 4 (TLR4), an innate immune receptor that triggers pro-inflammatory responses We hypothesize that presence of EDA+-FN in plasma promotes inflammation and accelerates atherosclerotic plaque formation. Model and Method: We generated EDA+/+/ApoE−/− mice, which contain optimized spliced sites at both splicing junctions of the EDA exon and constitutively express only EDA+-FN, and EDA−/−/ApoE−/− mice, which contain an EDA-null allele of the EDA exon and express only FN lacking EDA. ApoE−/−, EDA+/+/ApoE−/− and EDA−/−/ApoE−/− were fed a high-fat Western diet (21% fat and 0.2% cholesterol) beginning at 6 weeks until they were sacrificed at 5 months of age (i.e., 14 weeks on high-fat Western diet). We compared the extent of atherosclerosis in whole aortae, stained with Oil Red O and en face lesion area measured by morphometry, and in the cross section area of the aortic sinus using the VerHoeffs/Van Gieson stain. Results: We report that atherosclerotic plaque (% of total aorta) formation in the aorta of EDA+/+/ApoE−/− mice was increased by two-fold compared to control ApoE−/− mice (P<0.0001). Deletion of the alternatively spliced EDA domain in the ApoE−/− mice (EDA−/−/ApoE−/−) significantly reduced atherosclerotic plaque formation in the aorta (P<0.05) compared to ApoE−/− mice. Total cholesterol and triglycerides levels were similar in ApoE−/−, EDA+/+/ApoE−/− and EDA−/−/ApoE−/− mice. Similarly, atherosclerotic plaque formation was significantly increased in the aortic sinus of EDA+/+/ApoE−/− mice, intermediate in control ApoE−/− mice and reduced in EDA−/−/ApoE−/− mice (P<0.05). Additionally, we found that macrophage content, as analyzed by immunohistochemistry, was significantly elevated in the aortic root lesions of EDA+/+/ApoE−/− mice and reduced in EDA−/−/ApoE−/− mice compared to ApoE−/− mice (P<0.05). Moreover, EDA+-FN did not affect the sex-dependent regulation of atherosclerosis in ApoE−/− mice. Future experiments using EDA+/+/ApoE−/−/TLR4−/− are under progress to determine whether EDA+-FN exacerbate atherosclerosis via upregulating TLR4 signaling. Conclusions: Our findings reveal that EDA+-FN is pro-inflammatory and promotes atherosclerotic lesion formation and that monitoring plasma EDA+-FN might have prognostic value in patients at high risk for atherosclerosis. Disclosures: No relevant conflicts of interest to declare.

Spontaneous Atherosclerotic Lesions in TREM-Like Transcript-1 Deficient Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3312-3312
Author(s):  
Marieli Gonzalez ◽  
Fiorella Reyes ◽  
Deborah Marrero ◽  
A. Valance Washington
Keyword(s):  
Vessel Wall ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Atherogenic Diet ◽  
Chow Diet ◽  
Aortic Sinus ◽  
Platelet Surface ◽  
Atherosclerosis Progression ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels

Abstract Abstract 3312 It is well known that platelets, aside from regulating hemostasis, play an important role in inflammation-associated conditions like sepsis, viral infections, and atherosclerosis. In the latter, platelets not only form occlusive thrombi at lesions, but also play a role in the initiation of the disease by depositing activating molecules such as cytokines on the developing plaque. Although the mechanism by which platelet aggregation leads to occlusion is well-defined, the role of platelets in lesion initiation and progression is poorly understood and thus remains a gap in our knowledge. TLT-1 (Triggering Receptor Expressed in Myeloid cells (TREM)-like transcript-1) is a receptor exclusively found on megakarocytes and platelets that has a demonstrated effect in inflammatory responses. Upon platelet activation, TLT-1 is moved to the platelet surface along with p-selectin from the α-granules. Studies using the treml1−/− mouse demonstrated a predisposition to hemorrhage after an acute inflammatory challenge suggesting that TLT-1 may be a key regulatory molecule in the interface between hemostatic and inflammatory mechanisms and therefore should play a role in the development of atherosclerosis. Our original hypothesis was that evaluation of atherosclerosis lesions in the treml1−/− mouse would demonstrate fewer lesions and hence, a similar phenotype as the psel−/− mouse. Evaluation of 50 week old mice fed a chow diet surprisingly revealed spontaneous lesions in C57Bl/6 treml1−/− mice. Subsequent evaluation of cholesterol levels in treml1−/−mice on an atherogenic diet for four weeks demonstrated that they have significantly higher cholesterol levels when compared to WT mice. To evaluate atherosclerosis progression in TLT-1 deficiency, we developed the apoE−/−/treml1−/− double knockout mice and assessed lesion development after a four weeks atherogenic diet. Our results demonstrate that double null mice have exacerbated lesions when compared to the apoE −/− mice. Accordingly, 50 week old double null mice fed a chow diet also have larger atherosclerotic lesions in the aortic sinus than apoE −/− mice. These results clearly support a role for TLT-1 in dampening the progression of atherosclerosis. Current data from our laboratory suggest that TLT-1 may affect leukocyte function, therefore based on our model that TLT-1 deficiency leads to a heighted inflammatory state we hypothesized that treml1−/− mice will demonstrate greater leukocyte recruitment into the injured vessel wall, leading to greater deposition of factors that recruit more platelets and macrophages that later become foam cells. To delineate the mechanism by which TLT-1 affects atherosclerosis progression, we have evaluated neutrophil and monocyte infiltration into the vessel wall of the aortic sinus after four weeks atherogenic diet. The current state of our investigation is reported here. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Paraoxonase 2 Induces a Phenotypic Switch in Macrophage Polarization Favoring an M2 Anti-Inflammatory State

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Marie Koren-Gluzer ◽  
Mira Rosenblat ◽  
Tony Hayek
Keyword(s):  
Direct Effect ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Macrophage Polarization ◽  
Atherosclerotic Lesion ◽  
Peritoneal Macrophages ◽  
M2 Response ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Atherosclerosis Development

Inflammatory processes are involved in atherosclerosis development. Macrophages play a major role in the early atherogenesis, and they are present in the atherosclerotic lesion in two phenotypes: proinflammatory (M1) or anti-inflammatory (M2). Paraoxonase 2 (PON2) is expressed in macrophages, and it was shown to protect against atherosclerosis. Thus, the aim of our study was to analyze the direct effect of PON2 on macrophage inflammatory phenotypes. Ex vivo studies were performed with murine peritoneal macrophages (MPM) harvested from control C57BL/6 and PON2-deficient (PON2KO) mice. PON2KO MPM showed an enhanced proinflammatory phenotype compared to the control, both in the basal state and following M1 activation by IFNγand lipopolysaccharide (LPS). In parallel, PON2KO MPM also showed reduced anti-inflammatory responses in the basal state and also following M2 activation by IL-4. Moreover, the PON2-null MPM demonstrated enhanced phagocytosis and reactive oxygen species (ROS) production in the basal state and following M1 activation. The direct effect of PON2 was shown by transfecting human PON2 (hPON2) into PON2KO MPM. PON2 transfection attenuated the macrophages’ response to M1 activation and enhanced M2 response. These PON2 effects were associated with attenuation of macrophages’ abilities to phagocyte and to generate ROS. We conclude that PON2 promotes an M1 to M2 switch in macrophage phenotypes.

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