Effects of Berberine on Atherosclerosis

Atherosclerosis is an epidemic across the globe[A1], and its morbidity and mortality remain high, involving various complications and poor prognoses. In atherosclerosis, endothelial cells (ECs) dysfunction, vascular smooth muscle cells (VSMCs) migration and proliferation, foam cell formation, and inflammatory cell recruitment contribute to disease progression. Vascular stem cells (VSCs) also play a critical role in the cardiovascular system. Important data showed that the simultaneous increase of proliferation and apoptosis of VSMCs is the main cause of graft vein stenosis, suggesting that inhibition of VSMCs proliferation and apoptosis simultaneously is an important strategy for the treatment of atherosclerotic stenosis. Complementary and alternative medicine use among patients with cardiovascular disease (CVD) is growing. Berberine is an extract of Chinese traditional herbs that is known for its antimicrobial and anti-inflammatory effects in the digestive system. Its underlying anti-CVD mechanisms are currently attracting interest, and its pharmacological actions, such as antioxidation, regulation of neurotransmitters and enzymes, and cholesterol-lowering effects, have been substantiated. Recent studying found that berberine could inhibit both the proliferation and apoptosis of VSMCs induced by mechanical stretch stress simultaneously, which suggests that berberine might be an excellent drug to treat atherosclerosis. This review will focus on the recent progress of the effect of berberine on vascular cells, especially VSMCs, to provide important data and a new perspective for the application of berberine in anti-atherosclerosis.

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Mettl14 Mediates the Inflammatory Response of Macrophages in Atherosclerosis Through the NF-κB/IL-6 Signaling Pathway

10.21203/rs.3.rs-1070642/v1 ◽

2021 ◽

Author(s):

Yang Zheng ◽

Yunqi Li ◽

Xianwen Ran ◽

Di Wang ◽

Xianghui Zheng ◽

...

Keyword(s):

Inflammatory Response ◽

Signaling Pathway ◽

Foam Cell ◽

Epigenetic Modification ◽

Gene Knockout ◽

Critical Role ◽

Cell Formation ◽

Vital Role ◽

Foam Cell Formation

Abstract The inflammatory response of macrophages has been reported to play a critical role in atherosclerosis. The inflammatory state of macrophages is modified by epigenetic reprogramming. m6A RNA methylation is an epigenetic modification of RNAs. However, little is known about the potential roles and underlying mechanisms of m6A modification in macrophage inflammation. Herein, we showed that the expression of the m6A modification “writer” Mettl14 was increased in coronary heart disease and LPS-stimulated THP-1 cells. Knockdown of Mettl14 promoted M2 polarization of macrophages, inhibited foam cell formation and decreased migration. Mechanistically, the expression of Myd88 and IL-6 was decreased in Mettl14 knockdown cells. Through m6A modification, Mettl14 regulated the stability of Myd88 mRNA. Furthermore, Myd88 affected the transcription of IL-6 via the distribution of p65 in nuclei rather than directly regulating the expression of IL-6 through m6A modification. In vivo, Mettl14 gene knockout significantly reduced the inflammatory response of macrophages and the development of atherosclerotic plaques. Taken together, our data demonstrate that Mettl14 plays a vital role in macrophage inflammation in atherosclerosis via the NF-κB/IL-6 signaling pathway, suggesting that Mettl14 may be a promising therapeutic target for the clinical treatment of atherosclerosis.

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Regulation of foam cell formation, proliferation and apoptosis by Wnt signalling: implications for atherosclerosis

Atherosclerosis ◽

10.1016/j.atherosclerosis.2014.10.072 ◽

2014 ◽

Vol 237 (2) ◽

pp. e13

Author(s):

S. Simmonds ◽

J.L. Johnson ◽

A.C. Newby ◽

S.J. George

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Wnt Signalling ◽

Foam Cell Formation ◽

Proliferation And Apoptosis

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The Role of Microscopy in Understanding Atherosclerotic Lysosomal Lipid Metabolism

Microscopy and Microanalysis ◽

10.1017/s1431927603030010 ◽

2003 ◽

Vol 9 (1) ◽

pp. 54-67 ◽

Cited By ~ 20

Author(s):

W. Gray Jerome ◽

Patricia G. Yancey

Keyword(s):

Cultured Cells ◽

Foam Cell ◽

Critical Role ◽

Cell Formation ◽

Foam Cell Formation ◽

Cholesteryl Esters ◽

Normal Metabolism

Microscopy has played a critical role in first identifying and then defining the role of lysosomes in formation of atherosclerotic foam cells. We review the evidence implicating lysosomal lipid accumulation as a factor in the pathogenesis of atherosclerosis with reference to the role of microscopy. In addition, we explore mechanisms by which lysosomal lipid engorgement occurs. Low density lipoproteins which have become modified are the major source of lipid for foam cell formation. These altered lipoproteins are taken into the cell via receptor-mediated endocytosis and delivered to lysosomes. Under normal conditions, lipids from these lipoproteins are metabolized and do not accumulate in lysosomes. In the atherosclerotic foam cell, this normal metabolism is inhibited so that cholesterol and cholesteryl esters accumulate in lysosomes. Studies of cultured cells incubated with modified lipoproteins suggests this abnormal metabolism occurs in two steps. Initially, hydrolysis of lipoprotein cholesteryl esters occurs normally, but the resultant free cholesterol cannot exit the lysosome. Further lysosomal cholesterol accumulation inhibits hydrolysis, producing a mixture of cholesterol and cholesteryl esters within swollen lysosomes. Various lipoprotein modifications can produce this lysosomal engorgement in vitro and it remains to be seen which modifications are most important in vivo.

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Lack of mitochondrial NADP(H)-transhydrogenase expression in macrophages exacerbates atherosclerosis in hypercholesterolemic mice

Biochemical Journal ◽

10.1042/bcj20190543 ◽

2019 ◽

Vol 476 (24) ◽

pp. 3769-3789 ◽

Cited By ~ 2

Author(s):

Alessandro G. Salerno ◽

Thiago Rentz ◽

Gabriel G. Dorighello ◽

Ana Carolina Marques ◽

Estela Lorza-Gil ◽

...

Keyword(s):

Lipid Accumulation ◽

Double Mutant ◽

Foam Cell ◽

Critical Role ◽

Cell Formation ◽

Ldl Receptor ◽

Liver Mitochondria ◽

Cholesterol Homeostasis ◽

Foam Cell Formation ◽

Wild Type

The atherosclerosis prone LDL receptor knockout mice (Ldlr−/−, C57BL/6J background) carry a deletion of the NADP(H)-transhydrogenase gene (Nnt) encoding the mitochondrial enzyme that catalyzes NADPH synthesis. Here we hypothesize that both increased NADPH consumption (due to increased steroidogenesis) and decreased NADPH generation (due to Nnt deficiency) in Ldlr−/− mice contribute to establish a macrophage oxidative stress and increase atherosclerosis development. Thus, we compared peritoneal macrophages and liver mitochondria from three C57BL/6J mice lines: Ldlr and Nnt double mutant, single Nnt mutant and wild-type. We found increased oxidants production in both mitochondria and macrophages according to a gradient: double mutant > single mutant > wild-type. We also observed a parallel up-regulation of mitochondrial biogenesis (PGC1a, TFAM and respiratory complexes levels) and inflammatory (iNOS, IL6 and IL1b) markers in single and double mutant macrophages. When exposed to modified LDL, the single and double mutant cells exhibited significant increases in lipid accumulation leading to foam cell formation, the hallmark of atherosclerosis. Nnt deficiency cells showed up-regulation of CD36 and down-regulation of ABCA1 transporters what may explain lipid accumulation in macrophages. Finally, Nnt wild-type bone marrow transplantation into LDLr−/− mice resulted in reduced diet-induced atherosclerosis. Therefore, Nnt plays a critical role in the maintenance of macrophage redox, inflammatory and cholesterol homeostasis, which is relevant for delaying the atherogenesis process.

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PCSK9 and LRP5 in macrophage lipid internalization and inflammation

Cardiovascular Research ◽

10.1093/cvr/cvaa254 ◽

2020 ◽

Cited By ~ 1

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.

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Vav Protein Guanine Nucleotide Exchange Factor Regulates CD36 Protein-mediated Macrophage Foam Cell Formation via Calcium and Dynamin-dependent Processes

Journal of Biological Chemistry ◽

10.1074/jbc.m111.265082 ◽

2011 ◽

Vol 286 (41) ◽

pp. 36011-36019 ◽

Cited By ~ 25

Author(s):

S. Ohidar Rahaman ◽

Gang Zhou ◽

Roy L. Silverstein

Keyword(s):

Foam Cell ◽

Critical Role ◽

Cell Formation ◽

Foam Cell Formation ◽

Guanine Nucleotide ◽

Nucleotide Exchange ◽

Guanine Nucleotide Exchange ◽

Dependent Processes ◽

Dynamin 2

Atherosclerosis, a chronic inflammatory disease, results in part from the accumulation of modified lipoproteins in the arterial wall and formation of lipid-laden macrophages, known as “foam cells.” Recently, we reported that CD36, a scavenger receptor, contributes to activation of Vav-family guanine nucleotide exchange factors by oxidatively modified LDL in macrophages. We also discovered that CD36-dependent uptake of oxidized LDL (oxLDL) in vitro and foam cell formation in vitro and in vivo was significantly reduced in macrophages deficient of Vav proteins. The goal of the present study was to identify the mechanisms by which Vav proteins regulate CD36-dependent foam cell formation. We now show that a Vav-dynamin signaling axis plays a critical role in generating calcium signals in mouse macrophages exposed to CD36-specific oxidized phospholipid ligands. Chelation of intracellular Ca2+ or inhibition of phospholipase C-γ (PLC-γ) inhibited Vav activation (85 and 70%, respectively, compared with vehicle control) and reduced foam cell formation (approximately 75%). Knockdown of expression by siRNA or inhibition of GTPase activity of dynamin 2, a Vav-interacting protein involved in endocytic vesicle fission, significantly blocked oxLDL uptake and inhibited foam cell formation. Immunofluorescence microscopy studies showed that Vav1 and dynamin 2 colocalized with internalized oxLDL in macrophages and that activation and mobilization of dynamin 2 by oxLDL was impaired in vav null cells. These studies identified previously unknown components of the CD36 signaling pathway, demonstrating that Vav proteins regulate oxLDL uptake and foam cell formation via calcium- and dynamin 2-dependent processes and thus represent novel therapeutic targets for atherosclerosis.

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Abstract 431: Nlrp3 Inflammasome Inhibits Cholesterol Efflux in Macrophages by Downregulating Gpr109a Expression. A Novel Proatherogenic Mechanism

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.431 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Gantsetseg Tumurkhuu ◽

Jargalsaikhan Dagvadorj ◽

Wenxuan Zhang ◽

Timothy Crother ◽

Kenichi Shimada ◽

...

Keyword(s):

Aortic Root ◽

Nlrp3 Inflammasome ◽

Cholesterol Efflux ◽

Foam Cell ◽

Critical Role ◽

Cell Formation ◽

Foam Cell Formation ◽

Inflammasome Activation ◽

Efflux Transporter ◽

Nlrp3 Inflammasome Activation

Recent studies suggest that Nlrp3 inflammasome activation plays a critical role in the development of atherosclerosis and Chlamydia pneumoniae (Cpn ) infection has been shown to accelerate atherogenesis. Herein, we asked whether Cpn infection induced acceleration is via Nlrp3 inflammasome activation in hypercholestrolemia mouse model. Nlrp3 -/- Ldlr -/- , Casp1 -/- Ldlr -/- and Ldlr -/- mice were infected intranasally with Cpn followed by western diet (WD) for 16 weeks. Ldlr -/- mice infected with Cpn infection had markedly increased lesion size in the aortic sinus and aorta en face compared to WD only group. Casp1 activation in lesion macrophages in Ldlr -/- mice was also increased in Cpn group vs controls. Nlrp3 -/- Ldlr -/- or Casp1 -/- Ldlr -/- mice with and without Cpn resulted in significantly smaller of plaques in aortic root and aorta compare to Ldlr -/- mice. However, no difference was observed between Cpn infected and uninfected groups in the double knockout animals. Furthermore, foam cell formation of Nlrp3 -/- , and Casp1 -/- peritoneal macrophages after treatment with OxLDL and Cpn was significantly reduced when compared with WT cells. Interestingly, expression levels of the cholesterol efflux transporter, ATP-binding cassette A1 (ABCA1), was increased by RT PCR and western analysis in the KO macrophages. Further investigations found that the niacin receptor Gpr109a, a known positive regulator of ABCA1, was upregulated in Nlrp3 KO macrophages during foam cell formation. Hydroxy-butyrate, an activating ligand of GPR109, was produced by macrophages after Cpn infection indicating a feedback loop. Intact IL-1 signaling suppressed Gpr109a expression suggesting a pathway by which the inflammasome and IL-1β could enhance foam cell formation. In aortic root lesions, macrophage expression of Gpr109a was increased in Nlrp3 -/- Ldlr - - mice compare with Ldlr -/- mice on WD and infected with Cpn . In conclusion, the activation of the NLRP3 inflammasome negatively regulate Gpr109a receptor and its downstream cholesterol efflux transporter ABCA1, which leads to more foam cell formation and acceleration of atherosclerosis in Ldlr -/- mice. This work was supported by the National Institutes of Health grant HL111483 (to S. Chen)

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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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