scholarly journals Deletion or Inhibition of NOD1 Favors Plaque Stability and Attenuates Atherothrombosis in Advanced Atherogenesis

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2067 ◽  
Author(s):  
Silvia González-Ramos ◽  
Victoria Fernández-García ◽  
Miriam Recalde ◽  
Cristina Rodríguez ◽  
José Martínez-González ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Plaque Rupture ◽  
Primary Cultures ◽  
Cell Formation ◽  
Thin Layers ◽  
Foam Cell Formation ◽  
Aortic Sinus ◽  
Apoptotic Activity ◽  
Detection Of Biomarkers

Atherothrombosis, the main cause of acute coronary syndromes (ACS), is characterized by the rupture of the atherosclerotic plaque followed by the formation of thrombi. Fatal plaque rupture sites show large necrotic cores combined with high levels of inflammation and thin layers of collagen. Plaque necrosis due to the death of macrophages and smooth muscle cells (SMCs) remains critical in the process. To determine the contribution of the innate immunity receptor NOD1 to the stability of atherosclerotic plaque, Apoe−/− and Apoe−/− Nod1−/− atherosclerosis prone mice were placed on a high-fat diet for 16 weeks to assess post-mortem advanced atherosclerosis in the aortic sinus. The proliferation and apoptosis activity were analyzed, as well as the foam cell formation capacity in these lesions and in primary cultures of macrophages and vascular SMCs obtained from both groups of mice. Our results reinforce the preeminent role for NOD1 in human atherosclerosis. Advanced plaque analysis in the Apoe−/− atherosclerosis model suggests that NOD1 deficiency may decrease the risk of atherothrombosis by decreasing leukocyte infiltration and reducing macrophage apoptosis. Furthermore, Nod1−/− SMCs exhibit higher proliferation rates and decreased apoptotic activity, contributing to thicker fibrous caps with reduced content of pro-thrombotic collagen. These findings demonstrate a direct link between NOD1 and plaque vulnerability through effects on both macrophages and SMCs, suggesting promising insights for early detection of biomarkers for treating patients before ACS occurs.

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

scholarly journals Co-Delivery of Curcumin and Bioperine via PLGA Nanoparticles to Prevent Atherosclerotic Foam Cell Formation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1420 ◽  
Author(s):  
Sindhu C. Pillai ◽  
Ankita Borah ◽  
Minh Nguyen Tuyet Le ◽  
Hiroaki Kawano ◽  
Kouichi Hasegawa ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Atherosclerotic Plaque ◽  
Water Solubility ◽  
Foam Cell ◽  
Curcuma Longa ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Piper Nigrum ◽  
Foam Cell Formation ◽  
Nano Drug Delivery

Cholesterol-rich arterial plaques characterize atherosclerosis, a significant cause of heart disease. Nutraceuticals have received attention over the years, demonstrating potential benefits towards treating and preventing cardiovascular diseases (CVD), including atherosclerosis. Curcumin, a potent polyphenol present in Curcuma longa, has shown remarkable anti-atherosclerotic activity via anti-inflammatory and anti-oxidative properties. The bioavailability and low water solubility of curcumin limit its clinical translational purposes. These issues can be circumvented effectively by nano-drug delivery systems that can target atherosclerotic plaque sites. In this work, we chose to use curcumin and a natural bioenhancer called Bioperine (derived from Piper nigrum) inside a polymeric nano-drug delivery system for targeting atherosclerotic plaque sites. We selected two different ratios of curcumin:Bioperine to study its comparative effect on the inhibition of oxidized low-density lipoprotein (Ox-LDL)-induced foam cell formation. Our studies demonstrated that Cur-Bio PLGA NPs (both ratios) maintained the cell viability in THP-1 monocyte-derived macrophages above 80% at all periods. The 1:0.2:10 ratio of Cur-Bio PLGA NPs at a concentration of 250 μg/mL illustrated an enhanced reduction in the relative cholesterol content in the THP-1-derived foam cells compared to the 1:1:10 ratio. Confocal microscopy analysis also revealed a reduction in macrophage-mediated foam cell formation when administered with both the ratios of Cur-Bio PLGA NPs. Relative fold change in the mRNA expression of the genes involved in the inflammatory pathways in the atherosclerotic process downregulated NF-κB, CCL2/MCP-1, CD-36, and STAT-3 activity while upregulating the SCAR-B1 expression when treated with the Cur-Bio PLGA NPs. This study thus highlights the importance of natural-based compounds towards the therapeutic intervention against atherosclerotic activity when administered as preventive medicine.

scholarly journals Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion

2019 ◽  
Vol 5 (10) ◽  
pp. eaax9183 ◽  
Author(s):  
Jessica M. Johnston ◽  
Adrienn Angyal ◽  
Robert C. Bauer ◽  
Stephen Hamby ◽  
S. Kim Suvarna ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Strongly Correlated ◽  
Macrophage Phenotype ◽  
Chd Risk

Macrophages drive atherosclerotic plaque progression and rupture; hence, attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low-density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

scholarly journals Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion

2019 ◽  
Author(s):  
Jessica M Johnston ◽  
Adrienn Angyal ◽  
Robert C Bauer ◽  
Stephen Hamby ◽  
S Kim Suvarna ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Strongly Correlated ◽  
Macrophage Phenotype ◽  
Chd Risk

AbstractMacrophages drive atherosclerotic plaque progression and rupture, hence attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

scholarly journals Relationship Between Autophagy and Metabolic Syndrome Characteristics in the Pathogenesis of Atherosclerosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Jing Xu ◽  
Munehiro Kitada ◽  
Yoshio Ogura ◽  
Daisuke Koya
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Plaque Rupture ◽  
Cell Formation ◽  
Degradation Process ◽  
Vascular Wall ◽  
Foam Cell Formation ◽  
Plaque Instability

Atherosclerosis is the main cause of mortality in metabolic-related diseases, including cardiovascular disease and type 2 diabetes (T2DM). Atherosclerosis is characterized by lipid accumulation and increased inflammatory cytokines in the vascular wall, endothelial cell and vascular smooth muscle cell dysfunction and foam cell formation initiated by monocytes/macrophages. The characteristics of metabolic syndrome (MetS), including obesity, glucose intolerance, dyslipidemia and hypertension, may activate multiple mechanisms, such as insulin resistance, oxidative stress and inflammatory pathways, thereby contributing to increased risks of developing atherosclerosis and T2DM. Autophagy is a lysosomal degradation process that plays an important role in maintaining cellular metabolic homeostasis. Increasing evidence indicates that impaired autophagy induced by MetS is related to oxidative stress, inflammation, and foam cell formation, further promoting atherosclerosis. Basal and mild adaptive autophagy protect against the progression of atherosclerotic plaques, while excessive autophagy activation leads to cell death, plaque instability or even plaque rupture. Therefore, autophagic homeostasis is essential for the development and outcome of atherosclerosis. Here, we discuss the potential role of autophagy and metabolic syndrome in the pathophysiologic mechanisms of atherosclerosis and potential therapeutic drugs that target these molecular mechanisms.

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.

Abstract 474: Atherosclerotic Macrophages Develop a Progressive Lysosomal Dysfunction that can be Rescued by Induction of a Lysosomal Biogenesis Program

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Roy Emanuel ◽  
Ismail Sergin ◽  
Babak Razani
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Membrane Integrity ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Lysosomal Function ◽  
Lysosomal Dysfunction ◽  
Lipid Species

Recent reports of the proatherogenic phenotype of mice with a macrophage-specific autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique role of serving to process both exogenous material including the excess of atherogenic lipids and endogenous cargo including dysfunctional proteins and organelles. Surprisingly, little is known about the effect of an atherogenic environment on macrophage lysosomes. To address this, we utilize a variety of complementary techniques to show that oxidized LDL and cholesterol crystals, two of the commonly encountered lipid species in the atherosclerotic plaque, create a profound lysosomal dysfunction in cultured peritoneal macrophages. Disruptions in lysosomal pH, enzyme activity, proteolytic capacity, membrane integrity, and morphology are readily seen when cells are incubated with such lipids. Using flow cytometry to isolate resident tissue macrophages, we show that atherosclerotic plaque macrophages show features of dysfunctional lysosomes, a process that appears to be progressive with advanced plaque formation. These observations lead us to investigate whether stimulation of lysosomal function can ameliorate some of these effects. TFEB is the only known transcription factor that acts as a master regulator of lysosomal biogenesis, although its role in macrophages has not been studied. We show that overexpression of TFEB in cultured macrophages initiates a robust prodegradative response including induction of lysosomal genes and the generation of nascent lysosomes. Interestingly, this response can rescue several deleterious effects seen with atherogenic lipid loading including reductions in the secretion of the proinflammatory cytokine IL-1β and reductions in foam cell formation. Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program can have anti-atherogenic effects.

Targeting Hdac3 limits foam cell formation and improves atherosclerotic plaque stability

2014 ◽  
Vol 235 (2) ◽  
pp. e16-e17
Author(s):  
J. Van den Bossche ◽  
M.A. Hoeksema ◽  
M.J.J. Gijbels ◽  
S. van der Velden ◽  
A. Sijm ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Plaque Stability

PCSK9 and LRP5 in macrophage lipid internalization and inflammation

2020 ◽  
Author(s):  
Lina Badimon ◽  
Aureli Luquero ◽  
Javier Crespo ◽  
Esther Peña ◽  
Maria Borrell-Pages
Keyword(s):  
Nuclear Translocation ◽  
Foam Cell ◽  
Critical Role ◽  
Primary Cultures ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Blood Cholesterol ◽  
Foam Cell Formation ◽  
Lipid Uptake ◽  
Cholesterol Levels

Abstract Aims Atherosclerosis, the leading cause of cardiovascular diseases, is driven by high blood cholesterol levels and chronic inflammation. Low-density lipoprotein receptors (LDLR) play a critical role in regulating blood cholesterol levels by binding to and clearing LDLs from the circulation. The disruption of the interaction between proprotein convertase subtilisin/kexin 9 (PCSK9) and LDLR reduces blood cholesterol levels. It is not well known whether other members of the LDLR superfamily may be targets of PCSK9. The aim of this work was to determine if LDLR-related protein 5 (LRP5) is a PCSK9 target and to study the role of PCSK9 and LRP5 in foam cell formation and lipid accumulation. Methods and results Primary cultures of human inflammatory cells (monocytes and macrophages) were silenced for LRP5 or PCSK9 and challenged with LDLs. We first show that LRP5 is needed for macrophage lipid uptake since LRP5-silenced macrophages show less intracellular CE accumulation. In macrophages, internalization of LRP5-bound LDL is already highly evident after 5 h of LDL incubation and lasts up to 24 h; however, in the absence of both LRP5 and PCSK9, there is a strong reduction of CE accumulation indicating a role for both proteins in lipid uptake. Immunoprecipitation experiments show that LRP5 forms a complex with PCSK9 in lipid-loaded macrophages. Finally, PCSK9 participates in TLR4/NFkB signalling; a decreased TLR4 protein expression levels and a decreased nuclear translocation of NFκB were detected in PCSK9 silenced cells after lipid loading, indicating a downregulation of the TLR4/NFκB pathway. Conclusion Our results show that both LRP5 and PCSK9 participate in lipid uptake in macrophages. In the absence of LRP5, there is a reduced release of PCSK9 indicating that LRP5 also participates in the mechanism of release of soluble PCSK9. Furthermore, PCSK9 up-regulates TLR4/NFκB favouring inflammation.

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.

Sign in / Sign up

Export Citation Format

Share Document