Abstract 458: Fcgamma Receptor IV Expressed on Inflammatory Cells Drive Diet-induced Atherosclerosis in Hyperlipidemic Mouse Model

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Branimir Popovic ◽  
Doug Feck ◽  
Shanmugam Nagarajan
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Knockout Mice ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
Double Knockout ◽  
Arterial Lesions ◽  
Apoe Ko Mice ◽  
Progression Of Atherosclerosis ◽  
Apoe Ko

Objective: Functionally, Fcgamma receptors (FcgRs) can be classified as activating (FcgRI, III, and IV) and inhibitory (FcgRII) receptors. We have reported that combined deficiency of all three activating FcgRs in apoE knockout mice decreased atherosclerosis. In this report, we investigated the independent role of FcgRI and FcgRIV in the progression of atherosclerosis. We investigated the hypothesis that the deficiency of FcgRIV, one of the activating FcgRs, inhibits atherosclerosis in a hypercholesterolemic mouse model. We tested the hypothesis that FcgRI and FcgRIV exacerbate atherosclerosis using apoE-FcgRI dKO and apoE-FcgRIV deficient mice. Approach and Results: ApoE-FcgRI and apoE-FcgRIV double knockout mice (dKO) congenic to the C57BL/6 were generated and atherosclerotic lesions were assessed. Our results show that arterial lesions were not different between apoE-FcgRI dKO and apoE knockout (apoE KO) mice. Interestingly, arterial lesions were significantly decreased in a regular chow or a high-fat diet fed apoE-FcgRIV dKO male and female mice, relative to apoE KO mice. Bone marrow chimeras were used to address the relative contribution of FcgRIV expressed on hematopoietic cells including macrophages and dendritic cell. ApoE KO mice transplanted with apoE-FcgRIV dKO marrow showed significantly reduced arterial lesions relative to recipient mice transplanted with apoE KO marrow. Next, we investigated whether pro-inflammatory response contributed to the pro-atherogenic effect of FcgRIV. Activated CD4+ T cells of apoE-FcgRIV dKO mice showed increased secretion of IL-10, whereas IFN-gamma and IL-17 by T cells were decreased. Interestingly, dendritic cells at the lesion-prone vascular site from apoE-FcgRIV dKO mice induced increased IL-10 secretion by LDL-specific T cells. Moreover, FcgRIV KO and apoE-FcgRIV dKO macrophages showed decreased inflammasome activation as evidenced by decreased IL-1 beta response. Conclusions: Our findings demonstrate that the pro-inflammatory responses initiated by FcgRIV, one of the activating FcgRs, contribute to the progression of atherosclerosis.

Abstract 358: Factor Xa Deteriorates Atherosclerosis by Facilitating Inflammasome Formation via PAR-2-mediated Autophagy Suppression

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yasuhiro Maejima ◽  
Yusuke Ito ◽  
Natsuko Tamura ◽  
Masanori Konishi ◽  
Kenzo Hirao ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Critical Role ◽  
Atherosclerotic Lesion ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Inflammasome Activation ◽  
Apoe Ko Mice ◽  
Autophagy Activity ◽  
Apoe Ko

Background: It is known that an endogenous blood coagulation factor Xa (FXa) plays a critical role in facilitating atherosclerosis by activating protease-activated receptor-2 (PAR-2). However, the precise mechanism how FXa-mediated PAR-2 activation promotes atherogenesis remains to be elucidated. Purpose: The aim of this study is to explore how FXa promotes atherosclerosis through PAR-2-associated signaling pathway. Methods & Results: Administration of direct FXa inhibitor rivaroxaban (Riv; 120 mg/kg/day) to the mice significantly suppressed the plasma FXa activity compared with untreated mice. Administration of Riv to ApoE knockout mice fed with high fat diet (ApoE-KO-HFD) significantly reduced atherosclerotic area in the aorta compared with those in the untreated ApoE-KO-HFD. The plaque size of ApoE-KO mice crossed with PAR-2 knockout mice fed with HFD was similar to those of Riv-treated ApoE-KO-HFD. Ultrastructural examinations of atherosclerotic lesions revealed that the number of autophagosomes in the plaque-resident macrophages of Riv-treated ApoE-KO-HFD was significantly smaller than those of the untreated ApoE-KO-HFD. Immunostaining of NLRP3 revealed that Riv attenuated the inflammasome formation in the atherosclerotic lesion in ApoE-KO-HFD. In vitro experiments demonstrated that treatment of 7-ketocholesterol (7KC) markedly enhanced autophagy activity in the murine macrophages. The addition of FXa significantly promoted mTOR (Ser 2448 ) phosphorylation and blocked autophagy activity induced by 7KC, which was reversed in the presence of Riv (1 μM). Furthermore, immunoblot analyses demonstrated that FXa administration significantly accelerated inflammasome formation induced by 7KC, which was blocked in the presence of Riv. On the other hand, treatment with FXa failed to inhibit 7KC-induced autophagy and inflammasome activation in PAR-2-KO mice-derived macrophages. Conclusion: These results suggest that FXa worsens atherogenesis through PAR-2-mediated pathway by inhibiting macrophage autophagy which, in turn, promoting inflammasome activation.

Abstract 17182: The Role of ROS Sensitive TRPM2 Mediated Inflammation in Atherosclerosis

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Albert Yu ◽  
Zhichao Yue ◽  
Jianlin Feng ◽  
Hector Aguila ◽  
Lixia Yue
Keyword(s):  
Cardiovascular Diseases ◽  
Subclinical Atherosclerosis ◽  
Peritoneal Macrophages ◽  
Atherosclerotic Plaques ◽  
Atherosclerotic Cardiovascular Disease ◽  
Double Knockout ◽  
Trpm2 Channel ◽  
Apoe Ko Mice ◽  
Progression Of Atherosclerosis ◽  
Apoe Ko

Introduction: A variety of cardiovascular diseases stem from the manifestations of subclinical atherosclerosis, whose growth is fueled by inflammatory cytokines produced by macrophage-derived foam cells. A better understanding of the mechanisms underlying atherosclerosis will provide novel insights on potential therapeutic approaches for atherosclerosis associated cardiovascular diseases. The Ca 2+ -permeable TRPM2 which is activated by various reactive oxygen species (ROS) under stress conditions, is highly expressed in monocytes and macrophages. Our objective is to understand how TRPM2 in monocytes/macrophages mediates inflammation in atherosclerosis. Our hypothesis is that monocyte/macrophage TRPM2 is activated in the oxidative environment of atherosclerosis, and blocking TRPM2 will attenuates initiation and progression of atherosclerosis, thereby mitigating atherosclerotic cardiovascular disease. Methods: ApoE-deficient mice with Trpm2 deletion (APOE-TRPM2 double knockout: DKO) mice were fed with a high fat diet (HFD) to generate atherosclerosis. TRPM2 activity was measured by patch-clamp electrophysiology using peritoneal macrophages (PMs) obtained from DKO mice fed with HFD. Peripheral blood cells were collected from the tail vein and analyzed by flow cytometry. Results: We found that atherosclerosis plaque area was significantly reduced in HFD-fed DKO mice in comparison with the HFD-fed ApoE-KO mice (p<0.001). The TRPM2 channel activity and TRPM2 mediated Ca 2+ entry in macrophages were markedly higher in ApoE-KO mice fed with HFD than the ApoE-KO mice fed with normal chow, suggesting that TRPM2 may play a role in the atherosclerosis (p<0.05). Moreover, TRPM2 deletion drastically reduced IL-β production in PMs induced by LPS. Furthermore, we found that Trpm2-KO led to a 17% reduction of the inflammatory circulating myeloid cells in the ApoE-TRPM2 DKO mice compared to ApoE-KO mice fed with HFD (p<0.005). Conclusions: Our results indicate that deletion of TRPM2 reduces atherosclerotic plaques. Both inflammatory cytokine IL-1β production and inflammatory macrophages are reduced by TRPM2 deletion, indicating that the mechanisms by which TRPM2 inhibition deletion reduces atherosclerosis is through inhibiting inflammation during the atherosclerosis. As oxidative stress is a hallmark of atherosclerotic plaques, targeting monocyte/macrophage TRPM2 may serve as a novel approach to halt initiation and progression of atherosclerosis, as well as atherosclerotic cardiovascular diseases.

scholarly journals Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

2015 ◽  
Vol 112 (10) ◽  
pp. 3056-3061 ◽  
Author(s):  
Jayendra Kumar Krishnaswamy ◽  
Arpita Singh ◽  
Uthaman Gowthaman ◽  
Renee Wu ◽  
Pavane Gorrepati ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Knockout Mice ◽  
T Cell Response ◽  
Inflammasome Activation ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
Pyrin Domain ◽  
Proteomic Approach ◽  
Dendritic Cell Migration

Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.

Effects of Long-term Direct Thrombin Inhibition by Dabigatran Etexilate on Progression of Atherosclerosis in ApoE-/- and LDLR-/- Double-knockout Mice

2021 ◽  
Vol 5 (2) ◽  
Author(s):  
Hyodo K ◽  
◽  
Sanda T ◽  
Yoshimura M ◽  
Yamashita T ◽  
...  
Keyword(s):  
Placebo Group ◽  
Knockout Mice ◽  
Dabigatran Etexilate ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Tissue Type ◽  
Double Knockout ◽  
Progression Of Atherosclerosis ◽  
Inhibition Of Thrombin

Background: Atherosclerosis is characterized by a hypercoagulable state, during which coagulation and fibrinolytic factors are simultaneously activated. However, details regarding the progression of atherosclerosis remain unknown. Here, we investigated the effects of direct long-term inhibition of thrombin by dabigatran etexilate on atherosclerotic progression in apolipoprotein E–/– and low-density lipoprotein receptor–/– double-knockout mice. Methods: Mice received either standard chow (placebo group) or dabigatran-supplemented chow for 22 weeks. The amount of atherosclerosis was estimated as the ratio of the atherosclerotic area to the total aortic intimal area. Immunohistochemistry was used to examine the expression of Matrix Metalloproteinase-9 (MMP-9), Vascular Endothelial Growth Factor (VEGF), Tissue-Type Plasminogen Activator (t-PA), and Endothelial Nitric Oxide Synthase (eNOS) in atherosclerotic regions. Results: The atherosclerotic area was smaller in the dabigatran group than in the placebo group. Immunohistochemistry revealed decreased expression of MMP-9 and VEGF, but increased expression of eNOS, in the dabigatran group compared with the placebo group. t-PA expression did not differ between the groups. Conclusion: Direct long-term inhibition of thrombin by dabigatran in mice led to a decrease in atherosclerosis progression via decreased expression of MMP-9 and VEGF.

Tetrahydrobiopterin Slows the Progression of Atherosclerosis

Pteridines ◽  
2007 ◽  
Vol 18 (1) ◽  
pp. 115-121
Author(s):  
Suzuki Kunihiro ◽  
Yoshiyuki Hattori ◽  
Teruo Jojima ◽  
Atsuko Tomizawa ◽  
Toshie Okayasu ◽  
...  
Keyword(s):  
Drinking Water ◽  
Endothelial Dysfunction ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Oral Administration ◽  
Mrna Expression ◽  
Inflammatory Factors ◽  
Apoe Ko Mice ◽  
Progression Of Atherosclerosis ◽  
Apoe Ko

Abstract We investigated whether oral tetrahydrobiopterin (BH4) treatment might slow the progression of atherosclerosis using hypercholesterolemic ApoE-knockout (KO) mice. We report that ingesting BH4 in drinking water is effective to inhibit atherogenesis in mice. Furthermore, we report that BH4 treatment improves endothelial dysfunction and attenuates increased mRNA expression of NADPH oxidase components, as well as a number of inflammatory factors, such as LOX-1 and MCP-1, in the aortas of ApoE-KO mice. Strategies such as oral administration of BH4 to ensure continuous BH4 availability may be effective in restoring NO-mediated endothelial function and limiting vascular disease and the progression of atherosclerosis.

5219A novel senolytic drug, seno-7284 ameliorates age-related cardiometabolic diseases

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
G Katsuumi ◽  
I Katsuumi ◽  
M Suda ◽  
Y Yoshida ◽  
Y Hayashi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Knockout Mice ◽  
Biological Effects ◽  
Atherosclerotic Lesion ◽  
Clinical Settings ◽  
Mice Model ◽  
Cardiometabolic Diseases ◽  
Age Related ◽  
Apoe Ko Mice ◽  
Apoe Ko

Abstract Background Senescence at cellular level develops with various genotoxic stresses and it plays a pivotal role in aging and age-related disorders. Recently, it was shown that elimination of senescent cells, so called “senolysis” has potential to become a next generation therapy for age-related disorders including cardiovascular diseases, pulmonary emphysema, Alzheimer's diseases, etc. However, currently there is no senolytic agent available in clinical settings. Purpose Present study was aimed to identify a novel senolytic agent effective for cardiometabolic diseases in compounds already available in clinical settings. Here we demonstrate a compound called “seno-7284” exhibits senolytic effect in murine models of type 2 diabetes, atherosclerosis and progeroid. Methods We generated 1) diet-induced obase and diabetic model by imposing a high fat diet for two months, 2) atherosclerosis mice model by imposing western diet to ApoE homozygous knockout mice (ApoE-KO mice) for three months, and 3) Zmpste24 homozygous knockout mice (Zmpste24-KO mice) as a progeroid mice model. We administrated seno-7284 by mixing it into the diet (0.03% w/w). In one, two or four weeks after the administration of seno-7284 to each mice model, we collected tissue samples for further analyses. Results Seno-7284 reduced the accumulation of senescent cells in visceral adipose tissue of dietary obese mice as senescence-associated beta-galactosidase (SA-beta-gal) staining exhibits (Figure a). This effect was associated with the suppression in systemic glucose intolerance (Figure b), and adipose tissue inflammation in four weeks after the administration of seno-7284. Administrating seno-7284 for two weeks also reduced accumulation of senescent cells in atherosclerotic lesion in aorta of ApoE-KO mice (Figure c), and inhibited the progression of atherosclerosis (Figure d). Surprisingly, this drug significantly improved the lifespan of Zmpste24-KO mice by administering it from 12 weeks old. Further analysis including RNA-seq or metabolomic analysis suggested that seno-7284 stimulates endogenous senolytic function of NK cells and CD8+ T cells. Conclusion Our results indicate that seno-7284 mediates its biological effects by inducing senolysis in some murine aging models. Seno-7284 would become a promising therapeutic agent for age-related cardiometabolic diseases.

scholarly journals Melatonin Ameliorates the Progression of Atherosclerosis via Mitophagy Activation and NLRP3 Inflammasome Inhibition

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Sai Ma ◽  
Jiangwei Chen ◽  
Jing Feng ◽  
Ran Zhang ◽  
Miaomiao Fan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Inflammasome Activation ◽  
Ros Scavenging ◽  
Atherosclerotic Lesions ◽  
Autophagy Inhibitor ◽  
Nlrp3 Inflammasome Activation ◽  
Progression Of Atherosclerosis

The NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediated inflammatory responses are critically involved in the progression of atherosclerosis (AS), which is the essential cause for cardiovascular diseases. Melatonin has anti-inflammatory properties. However, little is known about the potential effects of melatonin in the pathological process of AS. Herein, we demonstrate that melatonin suppressed prolonged NLRP3 inflammasome activation in atherosclerotic lesions by reactive oxygen species (ROS) scavenging via mitophagy in macrophages. The atherosclerotic mouse model was induced with a high-fat diet using ApoE−/− mice. Melatonin treatment markedly attenuated AS plaque size and vulnerability. Furthermore, melatonin decreased NLRP3 inflammasome activation and the consequent IL-1β secretion within atherosclerotic lesions. Despite the unchanged protein expression, the silent information regulator 3 (Sirt3) activity was elevated in the atherosclerotic lesions in melatonin-treated mice. In ox-LDL-treated macrophages, melatonin attenuated the NLRP3 inflammasome activation and the inflammatory factors secretion, while this protective effect was abolished by either Sirt3 silence or autophagy inhibitor 3-MA. Mitochondrial ROS (mitoROS), which was a recognized inducer for NLRP3 inflammasome, was attenuated by melatonin through the induction of mitophagy. Both Sirt3-siRNA and autophagy inhibitor 3-MA partially abolished the beneficial effects of melatonin on mitoROS clearance and NLRP3 inflammasome activation, indicating the crucial role of Sirt3-mediated mitophagy. Furthermore, we demonstrated that melatonin protected against AS via the Sirt3/FOXO3a/Parkin signaling pathway. In conclusion, the current study demonstrated that melatonin prevented atherosclerotic progression, at least in part, via inducing mitophagy and attenuating NLRP3 inflammasome activation, which was mediated by the Sirt3/FOXO3a/Parkin signaling pathway. Collectively, our study provides insight into melatonin as a new target for therapeutic intervention for AS.

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