scholarly journals Dapagliflozin decreases atherosclerotic plaque instability via regulating macrophage pyroptosis

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
L Xu ◽  
Y Dai ◽  
K Yao ◽  
H Yang ◽  
A Sun ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Atherosclerotic Plaque ◽  
High Fat Diet ◽  
Foam Cell ◽  
Atherosclerotic Lesion ◽  
Plaque Formation ◽  
Public Institution ◽  
Foam Cell Formation ◽  
Diabetic Patients ◽  
High Fat

Abstract Background Vulnerable plaques are characterized by infiltration of inflammatory cells, playing a key role in the progression of acute coronary events. It's important to clarify the inflammatory mechanism of unstable plaque formation. Several clinical trials have demonstrated that dapagliflozin could reduce major adverse cardiac events in whether diabetic or non-diabetic patients. However, the underlying cardioprotective mechanism of dapagliflozin remains unclear. This study was aimed to investigate the role of dapagliflozin in regulating macrophage pyroptosis and vulnerable plaque formation. Methods 20 ApoE−/− mice (control) were fed with high fat diet while another 20 ApoE−/− mice were challenged with high fat diet plus dapagliflozin for 12 weeks. The extent and instability of atherosclerotic plaque was 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 dapagliflozin could inhibit plaque formation and reduce instability in ApoE−/− mice. FACS data showed that dapagliflozin could decrease CD11b+Ly6Chigh M1 macrophages differentiation and inhibit foam cells formation in ApoE−/− mice. Microarray analysis and in vitro studies exhibited that dapagliflozin could induce the down regulation of NLRP3, caspase-1, IL-1β, IL-18 and MMP-7/10/12/14 to retard macrophage pyroptosis and foam cell formation. Conclusions We have characterized a novel role for dapagliflozin in modulating atherosclerotic lesion development and progression. We envision that this study may provide several potential therapeutic targets for treatment of acute coronary syndromes. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Shanghai Sailing Program

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.

Abstract 249: Increased Vascular CCRL2 Expression by Disturbed Blood Flow Promotes Atherosclerotic Plaque Formation in ApoE Deficient Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Shuhong Hu ◽  
Li Zhu
Keyword(s):  
Blood Flow ◽  
Atherosclerotic Plaque ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Vascular Wall ◽  
Chronic Inflammatory Disease ◽  
Plaque Formation ◽  
Foam Cell Formation ◽  
Cell Trafficking

Atherosclerosis is a chronic inflammatory disease of the arterial wall elicited by accumulation of LDL and leucocytes in the subendothelium at predilection sites with disturbed laminar flow. Chemokines and their receptors appear to act as critical players in atherosclerosis as they not only direct atherogenic recruitment of leucocytes but also exert cell hemostatic functions by chemokine ligand-receptor axes and their specific or combined contributions. Atypical chemokine (C-C motif) receptor-like 2 (CCRL2) cooperates with its ligand chemerin and leukocyte-expressed chemerin receptor chemokine-like receptor 1 (CMKLR1) to regulate cell trafficking and inflammatory responses,but its role in atherosclerosis is not clear. To investigate whether CCRL2 contributes to the pathomechanism of atherogenesis, we generated CCRL2 -/- mice in hyperlipidemic atherosclerosis-prone ApoE -/- background and found that the atherosclerotic plaque area of the total aorta was significantly reduced compared with CCRL2 +/+ ApoE -/- mice on a high fat diet. The protective effect of CCRL2 deficiency was anatomically isolated primarily to the site of disturbed blood flow (D-flow) in the aortic arch but not in the descending aorta. Endothelial CCRL2 was upregulated in response to D-flow and either CCRL2 or CMKLR1 deletion reduced plaque formation. Further studies showed that CCRL2 co-localized with CMKLR1 and chemerin within the atherosclerotic aorta root. CCRL2 deficiency led to significantly less lipid deposition in aortic root, reduced CMKLR1 + leukocyte rolling on lesional vascular endothelium, diminished macrophage accumulation and foam cell formation, and polarized macrophage to an M2-like phenotype. These results demonstrate that D-flow induction of vascular CCRL2 is required for optimal formation of atherosclerotic plaques via coordinating the accumulation of CMKLR1 + monocytes/macrophages within the vascular wall, and thus identifies CCRL2 as a novel drug target to prevent or treat atherosclerosis. This work was supported by Natural Science Foundation of China (grant 81370373 to L.Z. and 31300781 to C.T.) Key Words: atherosclerosis, CCRL2, chemerin, macrophage

Abstract 451: Bone Marrow-derived Matricellular Protein CCN3 is Protective Against Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Chao Zhang ◽  
Xingjian Hu ◽  
Hong Shi ◽  
Wenconghui Wu ◽  
Yulan Qing ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Fat Diet ◽  
Immune Cell ◽  
Foam Cell ◽  
Reactive Oxygen Species Generation ◽  
Developed Countries ◽  
Foam Cell Formation ◽  
Matricellular Protein ◽  
High Fat ◽  
Double Knockout

Background: Atherosclerosis and its complications (myocardial infarction, stroke, peripheral vascular disease) are the major cause of morbidity and mortality in developed countries. Despite considerable efforts, the underlying pathomechanisms remain incompletely understood. In this study, we examined the role of a matricellular protein termed CCN3 in the pathogenesis of atherosclerosis. Methods and Results: To investigate whether CCN3 deficiency affects the development of atherosclerosis, control (ApoE-/-) and CCN3/ApoE double knockout mice were subjected to high fat diet feeding. In response to 16-week high fat diet feeding, the aortas of CCN3/ApoE double knockout (DKO) mice demonstrated exquisite susceptibility to atherosclerosis formation as evidenced by significantly increased size of aortic lipid-rich plaques in aortic roots, arch, thoracic and abdominal aorta. Concomitant with this, the atherosclerosis phenotype of DKO mice was manifested as follows: (1) a profoundly enhanced immune cell infiltration; (2) significantly increased expression of inflammatory markers; (3) heightened reactive oxygen species generation. Next, to address the cellular contributor(s) within or outside of the vessel wall responsible for the atherosclerosis phenotype, we performed reciprocal bone marrow transplantation (BMT) experiments. Transplantation of DKO bone marrow to ApoE-/- mice resulted in an increase of atherosclerosis formation, while transplantation of ApoE-/- marrow to DKO mice caused a reduction of atherosclerosis. These results indicate CCN3 deficiency in the bone marrow plays a major role in the development of atherosclerosis. Mechanistically, our cell-based studies in isolated macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect attributed to the modulation of key factors (e.g., increase of CD36, decrease of ABCG1) involved in lipoprotein transport. Conclusion: These results demonstrate bone marrow-derived CCN3 as an essential regulator of atherosclerosis and suggest the potential for future therapeutic strategies by manipulating CCN3 levels.

scholarly journals 12-Hydroxyeicosapentaenoic acid inhibits foam cell formation and ameliorates high-fat diet-induced pathology of atherosclerosis in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takahiro Nagatake ◽  
Yuki Shibata ◽  
Sakiko Morimoto ◽  
Eri Node ◽  
Kento Sawane ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Foam Cell ◽  
Linseed Oil ◽  
Cell Formation ◽  
Chronic Inflammatory Disease ◽  
Foam Cell Formation ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
High Fat ◽  
The Impact

AbstractAtherosclerosis is a chronic inflammatory disease associated with macrophage aggregate and transformation into foam cells. In this study, we sought to investigate the impact of dietary intake of ω3 fatty acid on the development of atherosclerosis, and demonstrate the mechanism of action by identifying anti-inflammatory lipid metabolite. Mice were exposed to a high-fat diet (HFD) supplemented with either conventional soybean oil or α-linolenic acid-rich linseed oil. We found that as mice became obese they also showed increased pulsatility and resistive indexes in the common carotid artery. In sharp contrast, the addition of linseed oil to the HFD improved pulsatility and resistive indexes without affecting weight gain. Histological analysis revealed that dietary linseed oil inhibited foam cell formation in the aortic valve. Lipidomic analysis demonstrated a particularly marked increase in the eicosapentaenoic acid-derived metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) in the serum from mice fed with linseed oil. When we gave 12-HEPE to mice with HFD, the pulsatility and resistive indexes was improved. Indeed, 12-HEPE inhibited the foamy transformation of macrophages in a peroxisome proliferator-activated receptor (PPAR)γ-dependent manner. These results demonstrate that the 12-HEPE-PPARγ axis ameliorates the pathogenesis of atherosclerosis by inhibiting foam cell formation.

Abstract 254: A Novel Role of Endothelial and Macrophage Epsins in Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Hong Chen
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Mapk Signaling ◽  
Leukocyte Recruitment ◽  
Foam Cell Formation ◽  
Tlr Signaling ◽  
M1 Macrophage

Background: Epsins are a family of ubiquitin-binding endocytic clathrin adaptors. We recently published that endothelial epsins function as critical regulators of tumor angiogenesis by controlling VEGF signaling (JCI, 2012; ATVB, 2013). Our goal is to define the novel role of epsins in endothelial cells (EC) and macrophages in regulating atherogenesis. Methods and Results: We engineered mice with specific deletion of epsins in EC (EC-DKO) or myeloid cells (MΦ-DKO). Strikingly, either EC-DKO or MΦ-DKO mice on ApoE-/- background fed western diet significantly reduced atherosclerotic lesion formation and foam cell accumulation. FACS analysis revealed that epsin deficiency greatly reduced TNFα and LPS-induced adhesion molecule expression (ICAM-1, VCAM-1, P- and E-selectins, CCR2 and MCP-1) in aortic EC and leukocyte recruitment in aorta. Mechanistically, EC epsins promote TNFR/TLR signaling and NF-κB and MAPK activation by recruiting NEMO, an essential NF-κB activator. In macrophages, epsin deficiency did not alter LDL scavenger receptors, CD36, Lox1 or SRB1, or reverse cholesterol transport proteins, ABCA1 or ABCG1, but did significantly reduce Lucifer Yellow pinocytosis, indicating a major defect in lipid uptake. Oil Red O staining of isolated ApoE-/-/MΦ-DKO macrophages showed little lipid accumulation, suggesting a mechanism in which epsin deficiency impairs foam cell formation. Epsin deficiency also significantly suppressed the pro-inflammatory M1 macrophage phenotype found in plaques thus suggesting an important pro-inflammatory role for epsins in macrophages. Loss of macrophage epsins significantly inhibited TNFα-stimulated activation of NF-κB and MAPK signaling pathways. We also observed a synthetic peptide comprising the epsin ubiquitin-interacting motif (UIM) and lesion homing sequence potently disrupted association of epsins with TNFR/TLR signaling complex in vitro, and inhibited atherosclerotic plaque in vivo. Conclusions: We demonstrate epsins promote atherogenesis by potentiating endothelium activation, leukocyte recruitment, foam cell formation and maintaining pro-inflammatory macrophages within the atherosclerotic plaque, thus suggesting epsins as a novel therapeutic target to combat atherogenesis.

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.

Abstract 141: The Loss of Nrf2 Enhances Vascular Inflammation but Reduces Atherosclerosis via Effects on Plasma Lipids in LDL Receptor Deficient Mice Fed High Fat Diet

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Anna-Kaisa Ruotsalainen ◽  
Emmi Tapper ◽  
Jari Lappalainen ◽  
Seppo Ylä-Herttuala ◽  
Anna-Liisa Levonen
Keyword(s):  
Bone Marrow ◽  
High Fat Diet ◽  
Foam Cell ◽  
Ldl Receptor ◽  
Total Loss ◽  
Foam Cell Formation ◽  
Systemic Effects ◽  
Related Factor ◽  
High Fat ◽  
Deficient Mice

OBJECTIVE Transcription factor NF-E2-related factor 2 (Nrf2) regulates antioxidant and detoxifying enzymes affording cytoprotection in the cardiovascular system. We have previously reported that Nrf2 deficiency specific to bone marrow derived cells aggravates atherosclerosis in LDL receptor deficient (LDLR-/-) mice. Furthermore, Nrf2 deficiency in macrophages enhances foam cell formation and promotes the proinflammatory phenotype. In contrast, the total loss of Nrf2 has been shown to protect against atherogenesis in apoE-deficient mice. The mechanism by which Nrf2 deficiency affords atheroprotection in apoE-model is currently unknown, but combined systemic and local vascular effects have been proposed. Given these contrasting results, we aimed at assessing the effect of total loss of Nrf2 on atherogenesis in hypercholesterolemic LDLR-/- mice. METHODS AND RESULTS Nrf2-/- mice were cross-bred to LDLR-/- mice and fed a high fat diet (HFD) for 6 or 12 weeks. The degree of atherosclerosis was assessed from the cross-sections of proximal aorta. Nrf2 deficiency decreased atherosclerosis in females from 17.2±8.7 % (mean ±SD, n=11-25) to 12.3±4.6 % (p=0.1) and in males from 11.2±3.9 % to 7.6±4.6 % (p=0.025) after 6 weeks on HFD. After 12 weeks on HFD the effects were more pronounced, as Nrf2 deficiency decreased atherosclerosis from 36.5±5.5 % to 30.3±3.5 % in females (p=0.001) and from 30.6±5.7 % to 21.3±6.9 % in males (p=0.005). Nrf2 deficiency also increased the macrophage content relative to lesion area. Supporting systemic effects, Nrf2 deficiency reduced plasma total cholesterol from 24.0±8.4 mmol/l to 10.6±6,7 mmol/l (p=0.006) and triglyceride levels from 3.6±1.4 mmol/l to 1.7±1.2 mmol/l (p=0.008) in males after 6 weeks on HFD. CONCLUSIONS In contrast to bone marrow specific Nrf2 deficiency, total loss of Nrf2 aggravates atherosclerosis in LDLR-/- mice likely via systemic effects on lipid metabolism.

scholarly journals TLR4-mediated inflammation promotes foam cell formation of vascular smooth muscle cell by upregulating ACAT1 expression

2014 ◽  
Vol 5 (12) ◽  
pp. e1574-e1574 ◽  
Author(s):  
Y-W Yin ◽  
S-Q Liao ◽  
M-J Zhang ◽  
Y Liu ◽  
B-H Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Atherosclerotic Plaque ◽  
Proinflammatory Cytokines ◽  
Foam Cell ◽  
Cell Formation ◽  
Plaque Formation ◽  
Foam Cell Formation ◽  
Atherosclerotic Plaque Formation

Abstract Vascular smooth muscle cell (VSMC) foam cell formation is an important hallmark, especially in advanced atherosclerosis lesions. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) promotes foam cell formation by promoting intracellular cholesteryl ester synthesis. The present study tests the hypothesis that oxidized low-density lipoprotein (oxLDL) increases the ACAT1 expression by activating the Toll-like receptor 4 (TLR4)-mediated inflammation, and ultimately promotes VSMC foam cell formation. Wild-type, ApoE−/−, TLR4−/− and ACAT1−/− mice on a C57BL/6J background were used. Increased TLR4, proinflammatory cytokines and ACAT1 were observed in high-fat (HF) diet-induced atherosclerotic plaque formation and in oxLDL-stimulated VSMCs. ACAT1 deficiency impeded the HF diet-induced atherosclerotic plaque formation and impaired the TLR4-manipulated VSMC foam cell formation in response to oxLDL. TLR4 deficiency inhibited the upregulation of myeloid-differentiating factor 88 (MyD88), nuclear factor-κB (NF-κB), proinflammatory cytokines and ACAT1, and eventually attenuated the HF diet-induced atherosclerotic plaque formation and suppressed the oxLDL-induced VSMC foam cell formation. Knockdown of MyD88 and NF-κB, respectively, impaired the TLR4-manipulated VSMC foam cell formation in response to oxLDL. Rosiglitazone (RSG) attenuated HF diet-induced atherosclerotic plaque formation in ApoE−/− mice, accompanied by reduced expression of TLR4, proinflammatory cytokines and ACAT1 accordingly. Activation of peroxisome proliferator-activated receptor γ (PPARγ) suppressed oxLDL-induced VSMC foam cell formation and inhibited the expression of TLR4, MyD88, NF-κB, proinflammatory cytokines and ACAT1, whereas inhibition of PPARγ exerted the opposite effect. TLR4−/− mice and VSMCs showed impaired atherosclerotic plaque formation and foam cell formation, and displayed no response to PPARγ manipulation. In conclusion, our data showed that oxLDL stimulation can activate the TLR4/MyD88/NF-κB inflammatory signaling pathway in VSMCs, which in turn upregulates the ACAT1 expression and finally promotes VSMC foam cell formation.

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