scholarly journals Myriocin and d-PDMP ameliorate atherosclerosis in ApoE−/− mice via reducing lipid uptake and vascular inflammation

2020 ◽  
Vol 134 (5) ◽  
pp. 439-458 ◽  
Author(s):  
Zemou Yu ◽  
Qing Peng ◽  
Songyue Li ◽  
Hongjun Hao ◽  
Jianwen Deng ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Vascular Inflammation ◽  
Cell Formation ◽  
Ldl Receptor ◽  
Foam Cell Formation ◽  
Lipid Uptake ◽  
Atherosclerosis Progression

Abstract Sphingolipids have been implicated in the etiology of atherosclerosis. The commonly used sphingolipid inhibitors, myriocin (a ceramide inhibitor) and d-PDMP (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glycosphingolipid inhibitor), have shown therapeutic potential but their efficacy and their underlying mechanisms remain unclear. Here, apolipoprotein E-deficient (apoE−/−) mice were fed a high-fat diet (HFD) and treated with a control, myriocin, d-PDMP, or atorvastatin for 12 weeks. We analyzed the effects of these drugs on the size and detailed composition of atherosclerotic plaques. Molecular biological approaches were used to explore how the inhibitors affect lipid metabolism and foam-cell formation. Treatment with myriocin or d-PDMP led to smaller and less vulnerable atherosclerotic lesions and was almost as effective as atorvastatin. Sphingolipid inhibitors down-regulated the expression of monocyte chemotactic protein 1 (MCP-1) and its receptor chemoattractant cytokine receptor 2 (CCR2), which play a key role in monocyte recruitment. They also decreased pro-inflammatory Ly-6chigh monocytes and influenced the uptake of modified LDL by down-regulating the expression of cluster of differentiation 36 (CD36) and lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1). The inhibitors exhibited the advantage of maintaining normal glucose homeostasis compared with atorvastatin. These findings reveal for the first time that the modulation of sphingolipid synthesis can effectively alleviate atherosclerosis progression by preventing lipid uptake and reducing inflammatory responses in the arterial walls.

scholarly journals PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation

2021 ◽  
Vol 8 ◽  
Author(s):  
Aureli Luquero ◽  
Lina Badimon ◽  
Maria Borrell-Pages
Keyword(s):  
Ldl Cholesterol ◽  
Foam Cell ◽  
Vascular Inflammation ◽  
Cell Formation ◽  
Plasma Lipid ◽  
Lipid Lowering ◽  
Foam Cell Formation ◽  
Hepatic Expression ◽  
Atherosclerosis Progression ◽  
The Impact

The relevance of PCSK9 in atherosclerosis progression is demonstrated by the benefits observed in patients that have followed PCSK9-targeted therapies. The impact of these therapies is attributed to the plasma lipid-lowering effect induced when LDLR hepatic expression levels are recovered after the suppression of soluble PCSK9. Different studies show that PCSK9 is involved in other mechanisms that take place at different stages during atherosclerosis development. Indeed, PCSK9 regulates the expression of key receptors expressed in macrophages that contribute to lipid-loading, foam cell formation and atherosclerotic plaque formation. PCSK9 is also a regulator of vascular inflammation and its expression correlates with pro-inflammatory cytokines release, inflammatory cell recruitment and plaque destabilization. Furthermore, anti-PCSK9 approaches have demonstrated that by inhibiting PCSK9 activity, the progression of atherosclerotic disease is diminished. PCSK9 also modulates thrombosis by modifying platelets steady-state, leukocyte recruitment and clot formation. In this review we evaluate recent findings on PCSK9 functions in cardiovascular diseases beyond LDL-cholesterol plasma levels regulation.

scholarly journals Myeloid-specific deficiency of pregnane X receptor decreases atherosclerosis in LDL receptor-deficient mice

2020 ◽  
Vol 61 (5) ◽  
pp. 696-706
Author(s):  
Yipeng Sui ◽  
Zhaojie Meng ◽  
Se-Hyung Park ◽  
Weiwei Lu ◽  
Christopher Livelo ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Ldl Receptor ◽  
Plasma Lipid ◽  
Pregnane X Receptor ◽  
Foam Cell Formation ◽  
Lipid Uptake ◽  
Atherosclerosis Development

The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRΔMyeLDLR−/−) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRΔMyeLDLR−/− mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRΔMyeLDLR−/− mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management.

Abstract 306: Deficiency of ROCK1 in Macrophages Protects Against Atherosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hong-Wei Wang ◽  
Naotsugu Oyama ◽  
Yoshiyuki Rikitake ◽  
Shiro Kitamoto ◽  
Jonathan Gitlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Foam Cell ◽  
Vascular Inflammation ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Low Density ◽  
Lipid Uptake

Background: Rho kinases (ROCKs) are serine-threonine protein kinases that regulate various cellular functions. There is increasing evidence that the RhoA/ROCK pathway plays an important pathophysiological role in cardiovascular diseases. However, direct evidence of which ROCK isoforms or target tissues are involved in the atherogenic process is still lacking. Objective: The aim of this study was to determine the effect of ROCK1 deficiency on atherogenesis and how ROCK1 affects key atherosclerosis-related macrophage function such as lipid uptake and chemotaxis. Methods: We utilized ROCK1 −/− mice and the atherosclerosis-prone apolipoprotein E knockout (apoE −/− ) mice or low-density lipoprotein receptor knockout (LDLR −/− ) mice to investigate the role of ROCK1 in the pathogenesis of atherosclerotic plaque formation. Bone marrow-derived macrophages from ROCK1 −/− and ROCK1 +/+ mice were used to investigate acetylated (Ac)LDL-mediated foam cell formation and chemotaxis. Results: Compared to atherosclerosis-prone apoE −/− mice, apoE −/− ROCK1 +/− mice had substantially less fatty streaks foam cells and atherosclerosis (77.0 ± 12.9 × 10 3 μm 2 versus 166.4 ± 14.6 × 10 3 μm 2 , P < 0.01). Atherosclerotic lesions were reduced also in LDLR −/− mice, whose bone marrow were replaced with bone marrow derived from ROCK1 −/− mice compared to ROCK1 +/+ recipients (181.5 ± 15.6 × 10 3 μm 2 versus 448.5 ± 33.3 × 10 3 μm 2 , P < 0.05). Bone marrow-derived ROCK1-deficient macrophages exhibited impaired chemotaxis to monocyte chemotactic protein-1 and showed reduced ability to take up lipids and to develop into foam cells when exposed to modified low density lipoprotein. Conclusion: These findings indicate that ROCK1 in macrophages is a critical mediator of foam cell formation, macrophage chemotaxis and atherogenesis, and suggest that macrophage ROCK1 may be an important therapeutic target for vascular inflammation and atherosclerosis.

Abstract 404: Induction of MiR133a Expression By IL-19 Targets LDLRAP1 and Reduces Oxidized LDL Uptake in VSMC

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Khatuna Gabunia ◽  
Allison Herman ◽  
Mitali Ray ◽  
Sheri Kelemen ◽  
Ross England ◽  
...  
Keyword(s):  
Foam Cell ◽  
Inflammatory Diseases ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Foam Cell Formation ◽  
Anti Inflammatory

Introduction: The transformation of vascular smooth muscle cells (VSMC) into foam cells leading to increased plaque size and decreased stability is a key, yet understudied step in atherogenesis. We reported that Interleukin-19 (IL-19), a novel, anti-inflammatory cytokine, attenuates atherosclerosis by anti-inflammatory effects on VSMC. We tested the hypothesis that one mechanism was reduction in VSMC foam cell formation. Methods and Results: In this work we report that IL-19 induces expression of miR133a, a muscle-specific miRNA, in VSMC. Although previously unreported, we show that miR133a can target and reduce mRNA abundance, mRNA stability, and protein expression of Low Density Lipoprotein Receptor Adaptor Protein 1, (LDLRAP1), an adaptor protein which functions to internalize the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the Autosomal Recessive Hypercholesterolemia (ARH) disorder in humans. We also show that IL-19 reduces lipid accumulation in VSMC, as well as LDLRAP1 expression and oxLDL uptake in a miR133a-dependent mechanism. We show that LDLRAP1 is expressed in plaque and neointimal VSMC of mouse and human injured arteries. Transfection of miR133a and LDLRAP1 siRNA into VSMC reduces their proliferation and uptake of oxLDL. miR133a is significantly increased in plasma from hyperlipidemic compared with normolipidemic patients. Summary and conclusions: miR133a targets LDLRAP1 3’UTR and reduces its expression. Expression of miR133a in IL-19 stimulated VSMC represents a previously unrecognized link between vascular lipid metabolism and inflammation, and may represent a therapeutic opportunity to combat vascular inflammatory diseases.

Dynamic Role of Macrophage Sub Types for Development of Atherosclerosis and Potential Use of Herbal Immunomodulators as Imminent Therapeutic Strategy

2020 ◽  
Vol 18 ◽  
Author(s):  
Parimalanandhini Duraisamy ◽  
Sangeetha Ravi ◽  
Mahalakshmi Krishnan ◽  
Catherene M. Livya ◽  
Beulaja Manikandan ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Atherosclerosis Progression ◽  
Proinflammatory Mediators ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Inflammatory Site

: Atherosclerosis, a major contributor to cardiovascular disease is a global alarm causing mortality worldwide. Being a progressive disease in the arteries, it mainly causes recruitment of monocytes to the inflammatory sites and subside pathological conditions. Monocyte-derived macrophage mainly acts in foam cell formation by engorging the LDL molecules, oxidizes it into Ox-LDL and leads to plaque deposit development. Macrophages in general differentiate, proliferate and undergo apoptosis at the inflammatory site. Frequently two subtypes of macrophages M1 and M2 has to act crucially in balancing the micro-environmental conditions of endothelial cells in arteries. The productions of proinflammatory mediators like IL-1, IL-6, TNF-α by M1 macrophage has atherogenic properties majorly produced during the early progression of atherosclerotic plaques. To counteract cytokine productions and M1-M2 balance, secondary metabolites (phytochemicals) from plants act as a therapeutic agent in alleviating atherosclerosis progression. This review summarizes the fundamental role of the macrophage in atherosclerotic lesion formation along with its plasticity characteristic as well as recent therapeutic strategies using herbal components and anti-inflammatory cytokines as potential immunomodulators.

scholarly journals Foam Cells as Therapeutic Targets in Atherosclerosis with a Focus on the Regulatory Roles of Non-Coding RNAs

2021 ◽  
Vol 22 (5) ◽  
pp. 2529
Author(s):  
Amin Javadifar ◽  
Sahar Rastgoo ◽  
Maciej Banach ◽  
Tannaz Jamialahmadi ◽  
Thomas P. Johnston ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Special Focus ◽  
Lipid Uptake ◽  
Therapeutic Goals ◽  
Expression Of Genes

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation.

Inhibitory effects of vasostatin-1 against atherogenesis

2018 ◽  
Vol 132 (23) ◽  
pp. 2493-2507 ◽  
Author(s):  
Yuki Sato ◽  
Rena Watanabe ◽  
Nozomi Uchiyama ◽  
Nana Ozawa ◽  
Yui Takahashi ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Inhibitory Effects ◽  
Macrophage Foam Cell ◽  
Down Regulation ◽  
Atherosclerotic Lesions

Vasostatin-1, a chromogranin A (CgA)-derived peptide (76 amino acids), is known to suppress vasoconstriction and angiogenesis. A recent study has shown that vasostatin-1 suppresses the adhesion of human U937 monocytes to human endothelial cells (HECs) via adhesion molecule down-regulation. The present study evaluated the expression of vasostatin-1 in human atherosclerotic lesions and its effects on inflammatory responses in HECs and human THP-1 monocyte-derived macrophages, macrophage foam cell formation, migration and proliferation of human aortic smooth muscle cells (HASMCs) and extracellular matrix (ECM) production by HASMCs, and atherogenesis in apolipoprotein E-deficient (ApoE−/−) mice. Vasostatin-1 was expressed around Monckeberg’s medial calcific sclerosis in human radial arteries. Vasostatin-1 suppressed lipopolysaccharide (LPS)-induced up-regulation of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HECs. Vasostatin-1 suppressed inflammatory M1 phenotype and LPS-induced interleukin-6 (IL-6) secretion via nuclear factor-κB (NF-κB) down-regulation in macrophages. Vasostatin-1 suppressed oxidized low-density lipoprotein (oxLDL)-induced foam cell formation associated with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) and CD36 down-regulation and ATP-binding cassette transporter A1 (ABCA1) up-regulation in macrophages. In HASMCs, vasostatin-1 suppressed angiotensin II (AngII)-induced migration and collagen-3 and fibronectin expression via decreasing ERK1/2 and p38 phosphorylation, but increased elastin expression and matrix metalloproteinase (MMP)-2 and MMP-9 activities via increasing Akt and JNK phosphorylation. Vasostatin-1 did not affect the proliferation and apoptosis in HASMCs. Four-week infusion of vasostatin-1 suppressed the development of aortic atherosclerotic lesions with reductions in intra-plaque inflammation, macrophage infiltration, and SMC content, and plasma glucose level in ApoE−/− mice. These results indicate the inhibitory effects of vasostatin-1 against atherogenesis. The present study provided the first evidence that vasostatin-1 may serve as a novel therapeutic target for atherosclerosis.

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 Anti-Atherosclerotic Activity of (3R)-5-Hydroxymellein from an Endophytic Fungus Neofusicoccum parvum JS-0968 Derived from Vitex rotundifolia through the Inhibition of Lipoproteins Oxidation and Foam Cell Formation

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 715
Author(s):  
Jae-Yong Kim ◽  
Soonok Kim ◽  
Sang Hee Shim
Keyword(s):  
Conformational Changes ◽  
Endophytic Fungus ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Ldl Oxidation ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Neofusicoccum Parvum

An endophytic fungus, Neofusicoccum parvum JS-0968, was isolated from a plant, Vitex rotundifolia. The chemical investigation of its cultures led to the isolation of a secondary metabolite, (3R)-5-hydroxymellein. It has been reported to have antifungal, antibacterial, and antioxidant activity, but there have been no previous reports on the effects of (3R)-5-hydroxymellein on atherosclerosis. The oxidation of lipoproteins and foam cell formation have been known to be significant in the development of atherosclerosis. Therefore, we investigated the inhibitory effects of (3R)-5-hydroxymellein on atherosclerosis through low-density lipoprotein (LDL) and high-density lipoprotein (HDL) oxidation and macrophage foam cell formation. LDL and HDL oxidation were determined by measuring the production of conjugated dienes and malondialdehyde, the amount of hyperchromicity and carbonyl content, conformational changes, and anti-LDL oxidation. In addition, the inhibition of foam cell formation was measured by Oil red O staining. As a result, (3R)-5-hydroxymellein suppressed the oxidation of LDL and HDL through the inhibition of lipid peroxidation, the decrease of negative charges, the reduction of hyperchromicity and carbonyl contents, and the prevention of apolipoprotein A-I (ApoA-I) aggregation and apoB-100 fragmentation. Furthermore, (3R)-5-hydroxymellein significantly reduced foam cell formation induced by oxidized LDL (oxLDL). Taken together, our data show that (3R)-5-hydroxymellein could be a potential preventive agent for atherosclerosis via obvious anti-LDL and HDL oxidation and the inhibition of foam cell formation.

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