scholarly journals ‘Blow my mind(in)’ – mindin neutralization for the prevention of atherosclerosis?

2018 ◽  
Vol 132 (14) ◽  
pp. 1509-1512
Author(s):  
Neil MacRitchie ◽  
Pasquale Maffia
Keyword(s):  
Vessel Wall ◽  
Cholesterol Efflux ◽  
Matrix Protein ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Extracellular Matrix Protein ◽  
Foam Cell Formation ◽  
Protective Effects ◽  
Inflammatory Microenvironment

The hallmark features of atherosclerosis include accumulation of low-density lipoprotein (LDL) carrying cholesterol in the vessel wall, formation of lipid-laden foam cells, and the creation of a pro-inflammatory microenvironment. To date, no effective treatments are clinically available for increasing cholesterol efflux from vascular macrophages and inducing reverse cholesterol transport (RCT). In an article published recently in Clinical Science (vol 132, issue 6, 1199-1213), Zhang and colleagues identified the extracellular matrix protein mindin/spondin 2 as a positive regulator of atherosclerosis. Genetic knockout of mindin in apolipoprotein-E (apoE)−/− mice attenuated atherosclerosis, foam cell formation, and inflammation within the vessel wall. Conversely, selective overexpression of mindin in macrophages in apoE−/− mice was sufficient to promote the greater severity of atherosclerosis. Interestingly, foam cell formation was closely associated with the expression of cholesterol transporters (ABCA1 and ACBG1) that facilitate cholesterol efflux. Liver X receptor (LXR)-β is a key modulator of cholesterol transporter expression and formed direct interactions with mindin. Furthermore, the protective effects of mindin deficiency on foam cell formation were blocked by inhibition of LXR-β. This article highlights a novel role of mindin in modulating foam cell formation and atherosclerosis development in mice through direct regulation of LXR-β. Thus far, direct targetting of LXR-β via pharmacological agonists has proven to be problematic due to the lack of subtype selective inhibitors and associated adverse effects. Indirect targetting of LXR-β, therefore, via mindin inhibition offers a new therapeutic strategy for increasing LXR-β induced cholesterol efflux, reducing foam cell formation, and preventing or treating atherosclerosis.

Abstract 43: Cholesterol Efflux Pathways Suppress Inflammasome Activation in Mice and Humans

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Marit Westerterp ◽  
Panagiotis Fotakis ◽  
Mireille Ouimet ◽  
Andrea E Bochem ◽  
Hanrui Zhang ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Loss Of Function ◽  
Caspase 1 ◽  
Macrophage Cholesterol Efflux

Plasma high-density-lipoprotein (HDL) has several anti-atherogenic properties, including its key role in functioning as acceptor for ATP-binding cassette A1 and G1 (ABCA1 and ABCG1) mediated cholesterol efflux. We have shown previously that macrophage Abca1/g1 deficiency accelerates atherosclerosis, by enhancing foam cell formation and inflammatory cytokine expression in atherosclerotic plaques. Macrophage cholesterol accumulation activates the inflammasome, leading to caspase-1 cleavage, required for IL-1β and IL-18 secretion. Several studies have suggested that inflammasome activation accelerates atherogenesis. We hypothesized that macrophage Abca1/g1 deficiency activates the inflammasome. In Ldlr -/- mice fed a Western type diet (WTD), macrophage Abca1/g1 deficiency increased IL-1β and IL-18 plasma levels (2-fold; P <0.001), and induced caspase-1 cleavage. Deficiency of the inflammasome components Nlrp3 or caspase-1 in macrophage Abca1/g1 knockouts reversed the increase in plasma IL-18 levels ( P <0.001), indicating these changes were inflammasome dependent. We found that macrophage Abca1/g1 deficiency induced caspase-1 cleavage in splenic CD115 + monocytes and CD11b + macrophages. While mitochondrial ROS production or lysosomal function were not affected, macrophage Abca1/g1 deficiency led to an increased splenic population of monocytes (2.5-fold; P <0.01). Monocytes secrete ATP, and as a result, ATP secretion from total splenic cells was increased (2.5-fold; P <0.01), likely contributing to inflammasome activation. Caspase-1 deficiency decreased atherosclerosis in macrophage Abca1/g1 deficient Ldlr -/- mice fed WTD for 8 weeks (225822 vs 138606 μm 2 ; P <0.05). Of therapeutic interest, one injection of reconstituted HDL (100 mg/kg) in macrophage Abca1/g1 knockouts decreased plasma IL-18 levels ( P <0.05). Tangier disease patients, with a homozygous loss-of-function for ABCA1, showed increased IL-1β and IL-18 plasma levels (3-fold; P <0.001), suggesting that cholesterol efflux pathways also suppress inflammasome activation in humans. These findings suggest that macrophage cholesterol efflux pathways suppress inflammasome activation, possibly contributing to the anti-atherogenic effects of HDL treatment.

Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-β

2018 ◽  
Vol 132 (11) ◽  
pp. 1199-1213 ◽  
Author(s):  
Cheng Zhang ◽  
Juan-Juan Qin ◽  
Fu-Han Gong ◽  
Jing-Jing Tong ◽  
Wen-Lin Cheng ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Matrix Protein ◽  
Foam Cell ◽  
Cell Formation ◽  
Direct Interaction ◽  
Extracellular Matrix Protein ◽  
Mechanistic Study ◽  
Foam Cell Formation ◽  
Atheromatous Plaques ◽  
Inflammatory Processes

Mindin, which is a highly conserved extracellular matrix protein, has been documented to play pivotal roles in regulating angiogenesis, inflammatory processes, and immune responses. The aim of the present study was to assess whether mindin contributes to the development of atherosclerosis. A significant up-regulation of Mindin expression was observed in the serum, arteries and atheromatous plaques of ApoE−/− mice after high-fat diet treatment. Mindin−/−ApoE−/− mice and macrophage-specific mindin overexpression in ApoE−/− mice (Lyz2-mindin-TG) were generated to evaluate the effect of mindin on the development of atherosclerosis. The Mindin−/−ApoE−/− mice exhibited significantly ameliorated atherosclerotic burdens in the entire aorta and aortic root and increased atherosclerotic plaque stability. Moreover, bone marrow transplantation further demonstrated that mindin deficiency in macrophages was largely responsible for the alleviated atherogenesis. The Lyz2-mindin-TG mice exhibited the opposite phenotype. Mindin deficiency enhanced foam cell formation by increasing the expression of cholesterol effectors, including ABCA1 and ABCG1. The mechanistic study indicated that mindin ablation promoted LXR-β expression via a direct interaction. Importantly, LXR-β inhibition largely reversed the ameliorating effect of mindin deficiency on foam cell formation and ABCA1 and ABCG1 expression. The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-β.

scholarly journals Legumain Promotes Atherosclerotic Vascular Remodeling

2019 ◽  
Vol 20 (9) ◽  
pp. 2195 ◽  
Author(s):  
Nana Ozawa ◽  
Yuki Sato ◽  
Yukari Mori ◽  
Hiroko Masuda ◽  
Mao Yamane ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Matrix Protein ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Umbilical Vein ◽  
Cell Formation ◽  
Extracellular Matrix Protein ◽  
Foam Cell Formation ◽  
Atheromatous Plaques

Legumain, a recently discovered cysteine protease, is increased in both carotid plaques and plasma of patients with carotid atherosclerosis. Legumain increases the migration of human monocytes and human umbilical vein endothelial cells (HUVECs). However, the causal relationship between legumain and atherosclerosis formation is not clear. We assessed the expression of legumain in aortic atheromatous plaques and after wire-injury-induced femoral artery neointimal thickening and investigated the effect of chronic legumain infusion on atherogenesis in Apoe−/− mice. We also investigated the associated cellular and molecular mechanisms in vitro, by assessing the effects of legumain on inflammatory responses in HUVECs and THP-1 monocyte-derived macrophages; macrophage foam cell formation; and migration, proliferation, and extracellular matrix protein expression in human aortic smooth muscle cells (HASMCs). Legumain was expressed at high levels in atheromatous plaques and wire injury-induced neointimal lesions in Apoe−/− mice. Legumain was also expressed abundantly in THP-1 monocytes, THP-1 monocyte-derived macrophages, HASMCs, and HUVECs. Legumain suppressed lipopolysaccharide-induced mRNA expression of vascular cell adhesion molecule-1 (VCAM1), but potentiated the expression of interleukin-6 (IL6) and E-selectin (SELE) in HUVECs. Legumain enhanced the inflammatory M1 phenotype and oxidized low-density lipoprotein-induced foam cell formation in macrophages. Legumain did not alter the proliferation or apoptosis of HASMCs, but it increased their migration. Moreover, legumain increased the expression of collagen-3, fibronectin, and elastin, but not collagen-1, in HASMCs. Chronic infusion of legumain into Apoe−/− mice potentiated the development of atherosclerotic lesions, accompanied by vascular remodeling, an increase in the number of macrophages and ASMCs, and increased collagen-3 expression in plaques. Our study provides the first evidence that legumain contributes to the induction of atherosclerotic vascular remodeling.

scholarly journals Cholesterol Efflux Capacity of Apolipoprotein A-I Varies with the Extent of Differentiation and Foam Cell Formation of THP-1 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Kouji Yano ◽  
Ryunosuke Ohkawa ◽  
Megumi Sato ◽  
Akira Yoshimoto ◽  
Naoya Ichimura ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Capacity Measurement ◽  
Cholesterol Efflux Capacity ◽  
Apolipoprotein A ◽  
Significant Difference ◽  
Main Protein

Apolipoprotein A-I (apoA-I), the main protein component of high-density lipoprotein (HDL), has many protective functions against atherosclerosis, one of them being cholesterol efflux capacity. Although cholesterol efflux capacity measurement is suggested to be a key biomarker for evaluating the risk of development of atherosclerosis, the assay has not been optimized till date. This study aims at investigating the effect of different states of cells on the cholesterol efflux capacity. We also studied the effect of apoA-I modification by homocysteine, a risk factor for atherosclerosis, on cholesterol efflux capacity in different states of cells. The cholesterol efflux capacity of apoA-I was greatly influenced by the extent of differentiation of THP-1 cells and attenuated by excessive foam cell formation.N-Homocysteinylated apoA-I indicated a lower cholesterol efflux capacity than normal apoA-I in the optimized condition, whereas no significant difference was observed in the cholesterol efflux capacity between apoA-I in the excessive cell differentiation or foam cell formation states. These results suggest that cholesterol efflux capacity of apoA-I varies depending on the state of cells. Therefore, the cholesterol efflux assay should be performed using protocols optimized according to the objective of the experiment.

scholarly journals Naoxintong Retards Atherosclerosis by Inhibiting Foam Cell Formation Through Activating Pparα Pathway

2019 ◽  
Vol 18 (10) ◽  
pp. 698-710 ◽  
Author(s):  
Zeng Wang ◽  
Huairui Shi ◽  
Huan Zhao ◽  
Zhen Dong ◽  
Buchang Zhao ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Oxidized Low Density Lipoprotein ◽  
Beneficial Effects ◽  
Cell Accumulation ◽  
Ldl Uptake

Background: We recently reported that Naoxintong (NXT), a China Food and Drug Administration (FDA)-approved cardiac medicine, could reduce the plaque size, but the underlying mechanism remains elusive now. Objective: In this study, we investigated the effects of NXT on foam cell accumulation both in vivo and in vitro and explored related mechanisms. Method: THP-1 cells and bone marrow-derived macrophages were incubated with oxidized low-density lipoprotein (ox-LDL) with/without Naoxintong. ApoE-/- mice fed an atherogenic diet were administered to receive NXT for eight weeks. Macrophage-derived foam cell formation in plaques was measured by immunohistochemical staining. Expression of proteins was evaluated by Western blot. Lentivirus was used to knockdown PPARα in THP-1 cells. Results: After NXT treatment, foam cell accumulation was significantly reduced in atherosclerotic plaques. Further investigation revealed that oxidized low-density lipoprotein (ox-LDL) uptake was significantly decreased and expression of scavenger receptor class A (SR-A) and class B (SR-B and CD36) was significantly downregulated post-NXT treatment. On the other hand, NXT increased cholesterol efflux and upregulated ATP-binding cassette (ABC) transporters (ABCA-1 and ABCG-1) in macrophages. Above beneficial effects of NXT were partly abolished after lentiviral knockdown of PPARα. Conclusion: Our findings suggest that NXT could retard atherosclerosis by inhibiting foam cell formation through reducing ox-LDL uptake and enhancing cholesterol efflux and above beneficial effects are partly mediated through PPARα pathway.

scholarly journals Hesperetin inhibits foam cell formation and promotes cholesterol efflux in THP-1-derived macrophages by activating LXRα signal in an AMPK-dependent manner

2021 ◽  
Author(s):  
Xuanjing Chen ◽  
Dezhi Zou ◽  
Xiaoling Chen ◽  
Huanlin Wu ◽  
Danping Xu
Keyword(s):  
Cholesterol Efflux ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Foam Cell ◽  
Cell Formation ◽  
Underlying Mechanism ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Protective Effects ◽  
Macrophage Foam Cell

AbstractCholesterol efflux from macrophages is the first step of reverse cholesterol transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Hesperetin has been reported to exert several protective effects on cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism in macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin on foam cell formation and cholesterol efflux by using human macrophages, focusing on liver X receptor alpha (LXRα) and AMPK. We found that hesperetin treatment reduced foam cell formation, intracellular cholesterol levels and the cholesterol esterification rate, and increased cholesterol efflux in THP-1 macrophages. Hesperetin increased the levels of LXRα protein and its targets, including ABCA1, ABCG1, SR-BI, and phosphorylated-AMPK. Meanwhile, the hesperetin-induced increase in LXRα expression was further increased by the AMPK agonist and inhibited by an AMPK inhibitor. Meanwhile, hesperetin increased the levels of LXRα mRNA and its target genes, all of which were decreased in cells transfected with the AMPKα1/α2 small interfering RNA (siRNA). Furthermore, the hesperetin-induced inhibition of foam cell formation and promotion of cholesterol efflux were decreased by transfection of AMPKα1/α2 siRNA. In conclusions, We are the first to report that hesperetin activate AMPK in THP-1-derived macrophages. This activation upregulats LXRα and its targets, including ABCA1, ABCG1 and SR-BI, which significantly inhibits foam cell formation and promotes cholesterol efflux. Our results highlight the therapeutic potential of hesperetin to possibly reduce foam cell formation. This new mechanism might contribute the anti-atherogenic effects of hesperetin.

ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

2021 ◽  
pp. 107424842110236
Author(s):  
Dun Niu ◽  
Lanfang Li ◽  
Zhizhong Xie
Keyword(s):  
Therapeutic Target ◽  
Chloride Channels ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Molecular Structures ◽  
Foam Cell Formation ◽  
Endothelium Dysfunction ◽  
Atherosclerotic Process

Chloride channel 3 (ClC-3), a Cl−/H+ antiporter, has been well established as a member of volume-regulated chloride channels (VRCCs). ClC-3 may be a crucial mediator for activating inflammation-associated signaling pathways by regulating protein phosphorylation. A growing number of studies have indicated that ClC-3 overexpression plays a crucial role in mediating increased plasma low-density lipoprotein levels, vascular endothelium dysfunction, pro-inflammatory activation of macrophages, hyper-proliferation and hyper-migration of vascular smooth muscle cells (VSMCs), as well as oxidative stress and foam cell formation, which are the main factors responsible for atherosclerotic plaque formation in the arterial wall. In the present review, we summarize the molecular structures and classical functions of ClC-3. We further discuss its emerging role in the atherosclerotic process. In conclusion, we explore the potential role of ClC-3 as a therapeutic target for atherosclerosis.

scholarly journals Protective Effect of Lusianthridin on Hemin-Induced Low-Density Lipoprotein Oxidation

2021 ◽  
Vol 14 (6) ◽  
pp. 567
Author(s):  
Su Wutyi Thant ◽  
Noppawan Phumala Morales ◽  
Visarut Buranasudja ◽  
Boonchoo Sritularak ◽  
Rataya Luechapudiporn
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Raw 264.7 ◽  
Low Density ◽  
Lipoprotein Oxidation ◽  
Raw 264.7 Macrophage Cells ◽  
Low Density Lipoprotein Oxidation

Oxidation of low-density lipoprotein (LDL) plays a crucial role in the pathogenesis of atherosclerosis. Hemin (iron (III)-protoporphyrin IX) is a degradation product of hemoglobin that can be found in thalassemia patients. Hemin is a strong oxidant that can cause LDL oxidation and contributes to atherosclerosis in thalassemia patients. Lusianthridin from Dendrobium venustrum is a phenolic compound that possesses antioxidant activity. Hence, lusianthridin could be a promising compound to be used against hemin-induced oxidative stress. The major goal of this study is to evaluate the protective effect of lusianthridin on hemin-induced low-density lipoprotein oxidation (he-oxLDL). Here, various concentrations of lusianthridin (0.25, 0.5, 1, and 2 µM) were preincubated with LDL for 30 min, then 5 µM of hemin was added to initiate the oxidation, and oxidative parameters were measured at various times of incubation (0, 1, 3, 6, 12, 24 h). Lipid peroxidation of LDL was measured by thiobarbituric reactive substance (TBARs) assay and relative electrophoretic mobility (REM). The lipid composition of LDL was analyzed by using reverse-phase HPLC. Foam cell formation with he-oxLDL in RAW 264.7 macrophage cells was detected by Oil Red O staining. The results indicated that lusianthridin could inhibit TBARs formation, decrease REM, decrease oxidized lipid products, as well as preserve the level of cholesteryl arachidonate and cholesteryl linoleate. Moreover, He-oxLDL incubated with lusianthridin for 24 h can reduce the foam cell formation in RAW 264.7 macrophage cells. Taken together, lusianthridin could be a potential agent to be used to prevent atherosclerosis in thalassemia patients.

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