Crocin ameliorates atherosclerosis by promoting the reverse cholesterol transport and inhibiting the foam cell formation via regulating PPARγ/LXR-α

Nlrp3 inflammasome is activated in advanced human atherosclerotic plaques. Gasdermin D (GsdmD) serves as a final executor of Nlrp3 inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-b). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1b; antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/IL-1b; nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet clear. Here, we used in-vivo Nlrp3 inflammasome activation to show that the GsdmD-/- mice release ~80% less IL-1b; vs WT mice. The GsdmD-/- macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ~26% decrease vs. ~60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1b; dependent fashion. The GsdmD-/- mice were resistance to Nlrp3 inflammasome mediated defect in RCT, with ~32% reduction in plasma RCT vs. ~ 57% reduction in WT mice, ~ 17% reduction in RCT to liver vs. 42% in WT mice, and ~ 37% decrease in RCT to feces vs. ~ 61% in WT mice. The LDLr anti-sense oligonucleotides (ASO) induced hyperlipidemic mouse model showed role of GsdmD in promoting atherosclerosis. The GsdmD-/- mice exhibit ~42% decreased atherosclerotic lesion area in females and ~33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing WT mice showed the presence of cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD during atherosclerosis. Our data show that GsdmD mediates inflammation-induced defect in RCT and promotes atherosclerosis.

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Gasdermin D Mediates Inflammation-Induced Defects in Reverse Cholesterol Transport and Promotes Atherosclerosis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.715211 ◽

2021 ◽

Vol 9 ◽

Author(s):

Emmanuel Opoku ◽

Cynthia Alicia Traughber ◽

David Zhang ◽

Amanda J. Iacano ◽

Mariam Khan ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Reverse Cholesterol Transport ◽

Foam Cell ◽

Atherosclerotic Lesion ◽

Foam Cell Formation ◽

Cholesterol Transport ◽

Inflammasome Activation ◽

Lesion Area ◽

Induced Defects

Activation of inflammasomes, such as Nlrp3 and AIM2, can exacerbate atherosclerosis in mice and humans. Gasdermin D (GsdmD) serves as a final executor of inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-1β). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1β antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/AIM2 and IL-1β nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet fully clear. Here, we used in vivo Nlrp3 inflammasome activation to show that the GsdmD–/– mice release ∼80% less IL-1β vs. Wild type (WT) mice. The GsdmD–/– macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ∼26% decrease vs. ∼60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1β dependent fashion. The GsdmD–/– mice were resistant to Nlrp3 inflammasome mediated defect in RCT, with ∼32% reduction in plasma RCT vs. ∼57% reduction in WT mice, ∼17% reduction in RCT to liver vs. 42% in WT mice, and ∼37% decrease in RCT to feces vs. ∼61% in WT mice. The LDLr antisense oligonucleotides (ASO) induced hyperlipidemic mouse model showed the role of GsdmD in promoting atherosclerosis. The GsdmD–/– mice exhibit ∼42% decreased atherosclerotic lesion area in females and ∼33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing sections stained positive for the cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD in atherosclerotic plaques. Our data show that GsdmD mediates inflammation-induced defects in RCT and promotes atherosclerosis.

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Infliximab Reverses Suppression of Cholesterol Efflux Proteins by TNF-α: A Possible Mechanism for Modulation of Atherogenesis

BioMed Research International ◽

10.1155/2014/312647 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 18

Author(s):

Iryna Voloshyna ◽

Sangeetha Seshadri ◽

Kamran Anwar ◽

Michael J. Littlefield ◽

Elise Belilos ◽

...

Keyword(s):

Cholesterol Efflux ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Cholesterol Transport ◽

Tnf Α ◽

Atp Binding Cassette Transporters ◽

Modified Lipoproteins ◽

Control Set ◽

Necrosis Factor

Tumor necrosis factor- (TNF-)αis a proinflammatory proatherogenic cytokine. Infliximab, an anti-TNF-αmonoclonal antibody, is effective in treating rheumatoid arthritis. However, its impact on cardiovascular burden and lipid transport is unclear. The present study investigates the effect of TNF-αand infliximab on reverse cholesterol transport (RCT) proteins. Uptake of modified lipoproteins by macrophages in the vasculature leads to atherogenic foam cell formation. RCT is mediated by proteins including ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), liver X receptor- (LXR-)α, and 27-hydroxylase. RCT counteracts lipid overload by ridding cells of excess cholesterol. THP-1 human monocytes were incubated with either TNF-αalone or TNF-αwith infliximab. Expression of proteins involved in cholesterol efflux was analyzed. TNF-αsignificantly reduced both ABCA1 and LXR-αmRNA (to68.5±1.59%,P<0.05, and41.2±0.25%,P<0.01, versus control set as 100%, resp.). Infliximab nullified the TNF-αeffect. Results were confirmed by Western blot. Infliximab abolished the increase in foam cells induced by TNF-α. TNF-αtreatment significantly reduces ABCA1 and LXR-αexpression in monocytes, thus bringing about a proatherogenic state. The anti-TNF drug infliximab, commonly used in rheumatology, restored RCT proteins. This is the first report of an atheroprotective effect of infliximab on RCT in monocytes.

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Macrophage cholesterol transport: a critical player in foam cell formation

Annals of Medicine ◽

10.1080/07853890310008198 ◽

2003 ◽

Vol 35 (3) ◽

pp. 146-155 ◽

Cited By ~ 47

Author(s):

Saara Vainio ◽

Elina Ikonen

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Cholesterol Transport

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Apolipoprotein and LRP1-Based Peptides as New Therapeutic Tools in Atherosclerosis

Journal of Clinical Medicine ◽

10.3390/jcm10163571 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3571

Author(s):

Aleyda Benitez Amaro ◽

Angels Solanelles Curco ◽

Eduardo Garcia ◽

Josep Julve ◽

Jose Rives ◽

...

Keyword(s):

Targeted Delivery ◽

Foam Cell ◽

Cell Formation ◽

Experimental Models ◽

Foam Cell Formation ◽

Cholesterol Transport ◽

Mimetic Peptides ◽

Arterial Intima ◽

Therapeutic Tools ◽

Underlying Mechanisms

Apolipoprotein (Apo)-based mimetic peptides have been shown to reduce atherosclerosis. Most of the ApoC-II and ApoE mimetics exert anti-atherosclerotic effects by improving lipid profile. ApoC-II mimetics reverse hypertriglyceridemia and ApoE-based peptides such as Ac-hE18A-NH2 reduce cholesterol and triglyceride (TG) levels in humans. Conversely, other classes of ApoE and ApoA-I mimetic peptides and, more recently, ApoJ and LRP1-based peptides, exhibit several anti-atherosclerotic actions in experimental models without influencing lipoprotein profile. These other mimetic peptides display at least one atheroprotective mechanism such as providing LDL stability against mechanical modification or conferring protection against the action of lipolytic enzymes inducing LDL aggregation in the arterial intima. Other anti-atherosclerotic effects exerted by these peptides also include protection against foam cell formation and inflammation, and induction of reverse cholesterol transport. Although the underlying mechanisms of action are still poorly described, the recent findings suggest that these mimetics could confer atheroprotection by favorably influencing lipoprotein function rather than lipoprotein levels. Despite the promising results obtained with peptide mimetics, the assessment of their stability, atheroprotective efficacy and tissue targeted delivery are issues currently under progress.

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EM of human atherosclerosis: Aortic fatty streaks with transitional lesion features

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100123519 ◽

1992 ◽

Vol 50 (1) ◽

pp. 622-623

Author(s):

K. Florian Klemp ◽

J.R. Guyton

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Processing Technique ◽

Foam Cell Formation ◽

Tissue Preparation ◽

Electron Microscopic ◽

Extracellular Lipid ◽

Electron Microscopic Cytochemistry ◽

Human Atherosclerosis ◽

Clinically Significant

The earliest distinctive lesions in human atherosclerosis are fatty streaks (FS), characterized initially by lipid-laden foam cell formation. Fibrous plaques (FP), the clinically significant lesions, differ from FS in several respects. In addition to foam cells, the FP also exhibit fibromuscular proliferation and a necrotic core region rich in extracellular lipid. The possible transition of FS into mature FP has long been debated, however. A subset of FS described by Katz etal., was intermediate in lipid composition between ordinary FS and FP. We investigated this hypothesis by electron microscopic cytochemistry by employing a tissue processing technique previously described by our laboratory. Osmium-tannic acid-paraphenylenediamine (OTAP) tissue preparation enabled ultrastructural analysis of lipid deposits to discern features characteristic of mature fibrous plaques.

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