Abstract 444: Semaphorin3A Reduces Atherosclerotic Plaque Formation in ApoE Knock Out Mice Through Regulation of M2 Type Macrophage Migration

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Talin Ebrahimian ◽  
Maryam Heidari ◽  
David Simon ◽  
Hojatollah Vali ◽  
Craig A Mandato ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Inflammatory Diseases ◽  
Plaque Formation ◽  
Atherosclerotic Plaques ◽  
M2 Macrophages ◽  
Aortic Sinus ◽  
Knock Out ◽  
Atherosclerotic Plaque Formation ◽  
Beta 1 Integrin

Objective: Recent data point to an important immunomodulatory role for neural guidance molecules, including semaphorin 3a (Sema-3A), in inflammatory diseases. Sema-3A is a secreted member of the Sema family and is produced by several immune cells including macrophages. We found that Sema-3A receptors are expressed in macrophages and in atherosclerotic plaques. Approach and results: To investigate the role of Sema-3A in atherosclerosis, ApoE-/- mice were administered with a Sema-3A overexpressing or a control plasmid and were fed a high fat diet for 9 weeks. Sema-3A receptors were expressed in macrophages and atherosclerotic plaques. Our results show that Sema-3A overexpressing mice had significantly smaller atherosclerotic plaques than control mice in the aortic sinus (0.3±0.02 vs. 0.4±0.03 mm 2 ), the brachiocephalic artery (0.04±0.01 vs. 0.1±0.01 mm 2 ) and the aorta (9.5±1.4 vs 15.3±2.9%), assessed by oil red O staining. No differences were observed in plaque stability, measured by collagen and smooth muscle cell alpha-actin staining. However, there was significantly less (2-fold) macrophage content in the plaques of Sema-3A compared to control mice, associated with decreased circulating monocytes determined by flow cytometry as cd11b positive and Gr-1 negative cells (4.97±0.74 vs. 7.2±0.62%). To better define the involved mechanisms, we investigated macrophage function In vitro and found that recombinant Sema-3A increased by 4 fold migration of M2 but not M1 macrophages. In addition, active beta-1 integrin expression was significantly enhanced (2-fold) by Sema-3A in human M2 macrophages. Importantly, Sema-3A induced a significant increase (by 50%) of focal adhesion kinase phosphorylation. Conclusions: Our data show that Sema-3A prevents atherosclerotic plaque formation in ApoE -/- mice. This may be due in part to enhanced motility and function of M2 macrophages through regulation of beta-1 integrin.

P711Histamine promotes atherosclerotic plaque instability via STAT6-dependent macrophage pyroptosis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Xu ◽  
X Yang ◽  
S Ding ◽  
J Qian ◽  
J Ge
Keyword(s):  
Microarray Analysis ◽  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Atherosclerotic Lesion ◽  
Plaque Formation ◽  
Foam Cell Formation ◽  
Gene Expressions ◽  
Knock Out ◽  
Plaque Instability

Abstract Background Atherosclerotic plaque formation and rupture is the primary cause for cardiovascular diseases. It's known that cell death and inflammation are crucial processes leading to atherosclerosis, which involves an important role of histamine. The aim of the present study is to determine the function of signal transducer and activator of transcription 6 (STAT6) in histamine-induced macrophage pyroptosis and plaque instability. Methods We constructed APOE/STAT6 double knock out (DKO) mice via hybridization of ApoE−/− and STAT6−/− mice. 20 ApoE−/− mice (control) and 20 DKO mice were challenged with high-fat diet for 12 weeks while 10 in each group were intraperitoneally infused with histamine (400ug/kg) every other day. The extent and instability of atherosclerotic plaque were 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 histamine could promote plaque formation and vulnerability in ApoE−/− mice, whereas this effect was inhibited in DKO mice. FACS data showed that histamine injection could increase CD11b+Ly6Chigh M1 macrophages differentiation and pyroptosis and facilitate foam cells formation in ApoE−/− mice, which was also inhibited in DKO mice. Microarray analysis and in vitro studies exhibited that histamine could induce the up-regulation of pyrotosis-related proteins such as NLRP3, caspase-1 and MMPs via a STAT6-dependent pathway to promote macrophage pyroptosis and foam cell formation. Conclusions We have characterized a novel role for histamine in modulating atherosclerotic lesion development and progression. Moreover, our work have figured out the detailed mechanisms by which histamine modulates the pyroptosis of macrophages and the progress of unstable atherosclerotic plaques. We envision that this study may provide several potential therapeutic targets benefit for atherosclerosis treatment.

scholarly journals Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation

2021 ◽  
Author(s):  
Carina Mauersberger ◽  
Hendrik B Sager ◽  
Jana Wobst ◽  
Tan An Dang ◽  
Laura Lambrecht ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Guanylyl Cyclase ◽  
Leukocyte Adhesion ◽  
Vascular Inflammation ◽  
Soluble Guanylyl Cyclase ◽  
Plaque Formation ◽  
Allele Carrier ◽  
Atherosclerotic Plaque Formation ◽  
Angiopoietin 1

Aim: The role of platelets in atherosclerosis remains incompletely understood. Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here we sought to investigate the contribution of platelet sGC to atherosclerosis and the therapeutic potential of targeting sGC in atherosclerosis. Methods and Results: We genetically deleted sGC in platelets of atherosclerosis-prone Ldlr-/- mice. By intravital fluorescence microscopy such Pf4-Cre+Gucy1b1flox/floxLdlr-/- mice displayed enhanced leukocyte adhesion to atherosclerotic plaques in comparison with their litter mates. Moreover, histological and flow cytometry analyses revealed more numerous inflammatory leukocytes and larger plaque sizes in aortic tissue of Ldlr-/- mice lacking sGC in platelets. In vitro, supernatant from activated platelets lacking sGC promoted leukocyte adhesion to endothelial cells (EC) via enhanced EC activation. Using cytokine profiling, we identified reduced angiopoietin-1 release by Pf4-Cre+Gucy1b1flox/flox and human GUCY1A1 risk allele carrier platelets to be responsible for enhanced activation of EC and subsequent leukocyte adhesion. Pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced recruitment of adoptively transferred leukocytes in Ldlr-/- mice fed a Western diet. Pharmacological sGC stimulation further reduced atherosclerotic plaque formation and vascular inflammation. Conclusion: Loss of sGC in platelets contributes to atherosclerotic plaque formation via reduced release of the soluble factor angiopoietin-1 and, subsequently, enhanced leukocyte recruitment. Pharmacological sGC stimulation might represent a novel therapeutic strategy to prevent and treat CAD.

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.

scholarly journals ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. 2385-2391 ◽  
Author(s):  
Chintan Gandhi ◽  
Mohammad Moshahid Khan ◽  
Steven R. Lentz ◽  
Anil K. Chauhan
Keyword(s):  
Atherosclerotic Plaque ◽  
Leukocyte Adhesion ◽  
Vascular Inflammation ◽  
Fold Increase ◽  
Plaque Formation ◽  
Aortic Sinus ◽  
Atherosclerotic Lesions ◽  
Atherosclerotic Plaque Formation ◽  
Von Willebrand ◽  
Early Atherosclerosis

Abstract ADAMTS13, a metalloprotease, plays a pivotal role in preventing spontaneous microvascular thrombosis by cleaving hyperactive ultra large von Willebrand factor multimers into smaller, less active multimers. Reduced ADAMTS13 activity in plasma has been described in many diseases associated with systemic inflammation. It remains uncertain, however, whether ADAMTS13 contributes to disease pathogenesis or rather simply serves as an inflammation-associated marker. We hypothesized that, by decreasing vascular inflammation, ADAMTS13 reduces the development of early atherosclerotic plaques. Using intravital fluorescence microscopy, we observed excessive leukocyte adhesion and accelerated atherosclerotic plaque formation at the carotid sinus of Adamts13−/−/ApoE−/− mice compared with ApoE−/− mice fed a high-fat Western diet. At 4 months of age, there was a significant increase in atherosclerosis in the aorta and aortic sinus of Adamts13−/−/ApoE−/− mice compared with ApoE−/− mice. Interestingly, we detected a 2-fold increase in macrophage recruitment to the atherosclerotic plaque of the Adamts13−/−/ApoE−/− mice compared with ApoE−/− mice, suggesting that the atherosclerotic lesions in these mice were not only larger but also more inflammatory. These findings reveal a new functional role for the antithrombotic enzyme ADAMTS13 in reducing excessive vascular inflammation and plaque formation during early atherosclerosis.

scholarly journals Salidroside Decreases Atherosclerotic Plaque Formation in Low-Density Lipoprotein Receptor-Deficient Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Bu-Chun Zhang ◽  
Wei-Ming Li ◽  
Rong Guo ◽  
Ya-Wei Xu
Keyword(s):  
Atherosclerotic Plaque ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Plaque Formation ◽  
Lipid Lowering ◽  
Control Group ◽  
Active Components ◽  
Aortic Sinus ◽  
Atherosclerotic Plaque Formation

Salidroside is isolated fromRhodiola roseaand is one of the main active components inRhodiolaspecies. The present study was designed to evaluate the effects of Salidroside on atherosclerotic plaque formation in high-fat diet-(HFD-) fed female LDL receptor knockout (LDLr-/-) mice.LDLr-/-mice fed an atherogenic HFD for 12 weeks were divided into two groups. One group was administered Salidroside (50 mg/kg/oral gavage) daily for 8 weeks, while the control group was administered saline. Salidroside treatment reduced serum lipids levels and the plaque area through the arch to the abdominal aorta. Furthermore, Salidroside improved macrophage content and enhanced collagen and smooth muscle cells contents in the aortic sinus. These changes were associated with reduced MCP-1, VCAM-1, and VCAM-1 protein expression in atherosclerotic aortas. All these results suggest that Salidroside decreases atherosclerotic plaques formation via effects on lipid lowering and anti-inflammation in HFD-fed LDLr−/−mice.

scholarly journals Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation

2018 ◽  
Vol 38 (11) ◽  
pp. 2562-2575 ◽  
Author(s):  
Petteri Rinne ◽  
Raquel Guillamat-Prats ◽  
Martina Rami ◽  
Laura Bindila ◽  
Larisa Ring ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Plaque Formation ◽  
Macrophage Phenotype ◽  
Atherosclerotic Plaque Formation
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