scholarly journals Role of PCSK9 in Homocysteine-Accelerated Lipid Accumulation in Macrophages and Atherosclerosis in ApoE−/− Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Ping Jin ◽  
Dengfeng Gao ◽  
Guangzhi Cong ◽  
Ru Yan ◽  
Shaobin Jia
Keyword(s):  
Lipid Accumulation ◽  
Cholesterol Efflux ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Lesion Area ◽  
Atherosclerotic Lesions

Background: Homocysteine (Hcy) has been established as an independent risk factor for atherosclerosis, and the involvement of hyperhomocysteinemia (HHcy) in atherosclerotic lesions is complex. Proprotein convertase subtilisin kexin 9 (PCSK9) has vital importance in lipid metabolism, and its inhibitors have intense lipid-lowering and anti-atherosclerotic effects. However, the underlying effect of PCSK9 on HHcy-accelerated dyslipidemia of macrophages is still uncertain. The purpose of this study was to investigate the potential role of PCSK9 in Hcy-induced lipid accumulation and atherosclerotic lesions.Methods:In vitro, gene and protein expressions were assessed by real-time quantitative PCR and western blot in THP-1 macrophages with Hcy incubation. Lipid accumulation and cholesterol efflux were evaluated with Hcy treatment. SBC-115076 was used to examine the role of PCSK9 in ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1)-dependent cholesterol efflux. In vivo, lesion area, lipid deposition and collagen contents were determined in aortas of ApoE−/− mice under a methionine diet. SBC-115076 was subcutaneously injected to explore the potential effects of PCSK9 inhibition on alleviating the severity of HHcy-related atherosclerotic lesions.Results: In THP-1 macrophages, Hcy dose- and time-dependently promoted PCSK9 gene and protein levels without regulating the translation of Low-density lipoprotein receptor (LDLR). SBC-115076 used to inhibit PCSK9 largely alleviated lipid accumulation and reversed the cholesterol efflux to apolipoprotein-I(apoA-I) and high-density lipoprotein (HDL) mediated by ABCA1 and ABCG1. In ApoE−/− mice, methionine diet induced HHcy caused larger lesion area and more lipid accumulation in aortic roots. SBC-115076 reduced atherosclerotic severity by reducing the lesion area and lipid accumulation and increasing expressions of ABCA1 and ABCG1 in macrophages from atherosclerotic plaque. In addition, SBC-115076 decreased plasma Hcy level and lipid profiles significantly.Conclusion: PCSK9 promoted lipid accumulation via inhibiting cholesterol efflux mediated by ABCA1 and ABCG1 from macrophages and accelerated atherosclerotic lesions under HHcy treatment. Inhibiting PCSK9 may have anti-atherogenic properties in HHcy-accelerated atherosclerosis.

scholarly journals Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis

2020 ◽  
Author(s):  
Bhupesh Singla ◽  
Hui-Ping Lin ◽  
Alex Chen ◽  
WonMo Ahn ◽  
Pushpankur Ghoshal ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cholesterol Efflux ◽  
Matrix Protein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lymphatic Drainage ◽  
Control Treatment

Abstract Aims Impaired lymphatic drainage of the arterial wall results in intimal lipid accumulation and atherosclerosis. However, the mechanisms regulating lymphangiogenesis in atherosclerotic arteries are not well understood. Our studies identified elevated levels of matrix protein R-spondin 2 (RSPO2) in atherosclerotic arteries. In this study, we investigated the role of RSPO2 in lymphangiogenesis, arterial cholesterol efflux into lesion-draining lymph nodes (LNs) and development of atherosclerosis. Methods and results The effect of RSPO2 on lymphangiogenesis was investigated using human lymphatic endothelial cells (LEC) in vitro and implanted Matrigel plugs in vivo. Cellular and molecular approaches, pharmacological agents, and siRNA silencing of RSPO2 receptor LGR4 were used to investigate RSPO2-mediated signalling in LEC. In vivo low-density lipoprotein (LDL) tracking and perivascular blockade of RSPO2–LGR4 signalling using LGR4-extracellular domain (ECD) pluronic gel in hypercholesterolemic mice were utilized to investigate the role of RSPO2 in arterial reverse cholesterol transport and atherosclerosis. Immunoblotting and imaging experiments demonstrated increased RSPO2 expression in human and mouse atherosclerotic arteries compared to non-atherosclerotic controls. RSPO2 treatment inhibited lymphangiogenesis both in vitro and in vivo. LGR4 silencing and inhibition of RSPO2–LGR4 signalling abrogated RSPO2-induced inhibition of lymphangiogenesis. Mechanistically, we found that RSPO2 suppresses PI3K-AKT-endothelial nitric oxide synthase (eNOS) signalling via LGR4 and inhibits activation of the canonical Wnt-β-catenin pathway. ApoE−/− mice treated with LGR4-ECD developed significantly less atherosclerosis compared with control treatment. Finally, increased arterial lymphatic vessel density and improved lymphatic drainage of fluorescently labelled LDL to deep cervical LNs were observed in LGR4-ECD-treated mice. Conclusion These findings demonstrate that RSPO2 inhibits lymphangiogenesis via LGR4 and downstream impairment of AKT-eNOS-nitric oxide signalling. These results may also inform new therapeutic strategies to promote lymphangiogenesis and improve cholesterol efflux from atherosclerotic arteries.

scholarly journals Sagunja-Tang Improves Lipid Related Disease in a Postmenopausal Rat Model and HepG2 Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Hiroe Go ◽  
Jin Ah Ryuk ◽  
Hye Won Lee ◽  
In Sil Park ◽  
Ki-Jung Kil ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Cholesterol Synthesis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Protein Levels ◽  
Related Disease

The present study was conducted to investigate the effect of Sagunja-tang on the lipid related disease in a rat model of menopausal hyperlipidemia and lipid accumulation in methyl-β-cyclodextrin-induced HepG2 cells. Inin vivostudy using menopausal hyperlipidemia rats, Sagunja-tang reduced retroperitoneal and perirenal fat, serum lipids, atherogenic index, cardiac risk factor, media thickness, and nonalcoholic steatohepatitis score, when compared to menopausal hyperlipidemia control rats. In HepG2 cells, Sagunja-tang significantly decreased the lipid accumulation, total cholesterol levels, and low-density/very-low-density lipoprotein levels. Moreover, Sagunja-tang reversed the methyl-β-cyclodextrin-induced decrease in the protein levels of critical molecule involved in cholesterol synthesis, sterol regulatory element binding protein-2, and low-density lipoprotein receptor and inhibited protein levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase as well as activity. Phosphorylation level of AMP-activated protein kinase was stimulated by Sagunja-tang. These results suggest that Sagunja-tang has effect on inhibiting hepatic lipid accumulation through regulation of cholesterol synthesis and AMPK activityin vitro. These observations support the idea that Sagunja-tang is bioavailable bothin vivoandin vitroand could be developed as a preventive and therapeutic agent of hyperlipidemia in postmenopausal females.

Abstract 5: Lipid Droplet Associated Hydrolase: A New Player in Cholesterol Mobilization From Foam Cells

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Younghwa Goo ◽  
Pradip Saha ◽  
Larry Chan ◽  
Antoni Paul
Keyword(s):  
Lipid Droplet ◽  
Cholesterol Efflux ◽  
Bone Marrow Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Peritoneal Macrophages ◽  
Cholesterol Homeostasis

Lipid laden macrophages/foam cells are a hallmark of atherosclerotic lesions from early to late stages of development. Macrophages take-up modified low-density lipoprotein (mLDL) particles and store surplus mLDL-derived cholesterol as cholesterol ester (CE) in cytoplasmic lipid droplets (LDs). Accelerating CE hydrolysis from the LDs is a plausible strategy to promote reverse cholesterol transport from the atheroma. However, the identity of the CE hydrolases that function on LDs remains unknown. Previously we identified lipid droplet-associated hydrolase (LDAH) in LDs purified from macrophages and reported that in vitro LDAH regulates CE levels by increasing CE hydrolysis. To determine the relevance of LDAH in atherogenesis, we have generated LDAH knockout (LDAH-/-) mice. Mouse peritoneal macrophages (MPM) isolated from LDAH-/- mice had increased cytoplasmic LDs, increased net CE content, and decreased cholesterol efflux. In atherosclerosis studies, both male and female LDAH-/- mice crossed with apolipoprotein E knockout (apoE-/-) mice fed a Western diet developed larger lesions. Lesions of LDAH-/-/ apoE-/- mice were characterized by increased areas of macrophages containing enlarged cytoplasms with large LDs. Supporting a direct atheroprotective role of LDAH in macrophages, lesions of apoE-/- mice that received bone marrows from LDAH-/-/apoE-/- mice progressed faster than those that received bone marrow cells from LDAH+/+/apoE-/- mice. In qPCR analyses of genes involved in cholesterol homeostasis in macrophages, we found that ABC binding cassette transporters ABCA1 and ABCG1, which mediate cholesterol efflux through the plasma membrane, were consistently decreased in LDAH-/- MPM. Further in vivo gene expression studies on macrophages selectively obtained from lesions using laser capture microdissection are underway. In conclusion, our study suggests that LDAH promotes LD CE hydrolysis and cholesterol efflux from foam cells within the atheroma, and uncovers a potential target to promote reverse cholesterol from arteries as a means of ameliorating atherosclerosis development.

scholarly journals Metformin Ameliorates Ethanol-Induced Liver Triglyceride Accumulation by LKB1/AMPK/ACC Pathway

2021 ◽  
Author(s):  
Fotian Xie ◽  
Dongmei Wang ◽  
Kwok Fai So ◽  
Jia Xiao ◽  
Yi Lv
Keyword(s):  
Lipid Accumulation ◽  
Therapeutic Potential ◽  
Lipid Lowering ◽  
Liver Triglyceride ◽  
Hepatic Lipid Accumulation ◽  
Triglyceride Accumulation ◽  
Lipid Formation

Abstract Background: Hepatic lipid accumulation is one of the main pathological features of alcoholic liver disease. Metformin is an AMPK activator that has been shown to have lipid lowering effects. The purpose of this study was to investigate whether metformin had a beneficial effect on lipid accumulation in the pathogenesis of ALD.Methods: AML12 cells and male C57BL/6 mice were used to establish ALD models in vitro and in vivo, respectively. The effects of metformin on hepatocyte lipid accumulation and ALD progression in mice were detected. The role of LKB1/AMPK/ACC axis in metformin against ethanol-induced lipid accumulation was evaluated by siRNA and AAV-shRNA interference.Results: Metformin reduced the ethanol-induced lipid accumulation in AML12 cells through activating AMPK/ACC and SREBP1c and inhibiting PPARα. In addition, compared with control mice, metformin treatment inhibited ethanol-induced liver adipose accumulation and the increase of ALT and AST in serum. Interference with LKB1 attenuated the effect of metformin on ethanol-induced lipid accumulation both in vitro and in vivo.Conclusion: Metformin protects against lipid formation in ALD by activating LKB1/AMPK/ACC axis. Thus, metformin has therapeutic potential for the prevention of ALD.

Abstract 908: In Vivo Role of the Pharmacogenetics of Glucuronidation in the Disposition and Triglyceride Response to Fenofibrate

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Robert J Straka ◽  
Na Li ◽  
Chantal Guillemette ◽  
Michael Y Tsai ◽  
Naomi Q Hanson ◽  
...  
Keyword(s):  
Steady State ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Fenofibric Acid ◽  
Lipid Response ◽  
Study Participants

In spite of optimal low-density lipoprotein (LDL-C) lowering with statins, cardiovascular risk remains high for patients with elevated triglyceride (TG)-low high-density cholesterol (HDL-C) profiles. Fenofibric acid, the active moiety of fenofibrate, acts on the peroxisome proliferator-activated nuclear receptor-alpha (PPAR-α) to lower TG and raise HDL-C. The extent of lipid response has been shown to be associated with serum concentrations (conc.) of fenofibric acid. In vitro work confirms fenofibric acid is primarily eliminated by UDP-glucuronosyltransferases (UGTs) including UGT2B7, and others (UGT1A1, UGT1A3 and UGT1A9). Therefore, we hypothesized genetic variations in UGT activity may be associated with fenofibric acid conc. and thus may influence lipid response. Purpose: To test if the A-327G SNP (rs7662029) for UGT2B7, which has been shown to modulate UGT2B7 expression in vitro, is associated with serum conc. of fenofibric acid and TG response in vivo . Methods: As part of the NHLBI sponsored Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, participants providing consent and not currently taking lipid lowering medications, were analyzed for fasting lipid response pre and post 21 days of once daily 160mg fenofibrate. TG response was calculated by the log of the ratio of the average of the 2 pre- and post-fenofibrate exposure TG determinations. Associations between UGT2B7 A-327G genotype and steady-state trough fenofibric acid conc. as well as TG response were analyzed by linear regression. Results : 745 participants (51% male) with both genotype and phenotype data were included. The mean (SD) age was 49 (16) years and the median (25 th ,75 th percentile) % change in TG concentrations was -32.3 (−45.2, −19.0). The G allele frequency for UGT2B7A>G was 0.49 and was in HWE (p = 0.8). After adjusting for age, age 2 , sex, alcohol use, height and serum creatinine, strong associations were observed between UGT2B7 A-327G genotypes and steady-state trough fenofibric acid conc. (log-transformed, p = 4 × 10 −8 ) as well as TG response (p = 0.002, also adjusted for baseline TG). Conclusion : This study suggests UGT2B7 A-327G genotype may contribute to TG response by way of influencing glucuronidation activity of fenofibric acid.

scholarly journals Wide Biological Role of Hydroxytyrosol: Possible Therapeutic and Preventive Properties in Cardiovascular Diseases

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1932
Author(s):  
Chiara D’Angelo ◽  
Sara Franceschelli ◽  
José Luis Quiles ◽  
Lorenza Speranza
Keyword(s):  
Cardiovascular Health ◽  
Biological Effects ◽  
Low Density Lipoprotein ◽  
Antioxidant Properties ◽  
Density Lipoprotein ◽  
In Vivo Models ◽  
And Oxidative Stress

The growing incidence of cardiovascular disease (CVD) has promoted investigations of natural molecules that could prevent and treat CVD. Among these, hydroxytyrosol, a polyphenolic compound of olive oil, is well known for its antioxidant, anti-inflammatory, and anti-atherogenic effects. Its strong antioxidant properties are due to the scavenging of radicals and the stimulation of synthesis and activity of antioxidant enzymes (SOD, CAT, HO-1, NOS, COX-2, GSH), which also limit the lipid peroxidation of low-density lipoprotein (LDL) cholesterol, a hallmark of atherosclerosis. Lowered inflammation and oxidative stress and an improved lipid profile were also demonstrated in healthy subjects as well as in metabolic syndrome patients after hydroxytyrosol (HT) supplementation. These results might open a new therapeutic scenario through personalized supplementation of HT in CVDs. This review is the first attempt to collect together scientific literature on HT in both in vitro and in vivo models, as well as in human clinical studies, describing its potential biological effects for cardiovascular health.

scholarly journals Arterial heparin deposition: role of diffusion, convection, and extravascular space

1998 ◽  
Vol 275 (6) ◽  
pp. H2236-H2242 ◽  
Author(s):  
Mark A. Lovich ◽  
Mike Philbrook ◽  
Sean Sawyer ◽  
Ed Weselcouch ◽  
Elazer R. Edelman
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Perivascular Space ◽  
Low Density ◽  
Pressure Gradients ◽  
Extravascular Space ◽  
Diffusion Convection

Transvascular transport has been studied with atherogenic, tracer, and inert compounds such as low-density lipoprotein, horseradish peroxidase, and albumin, respectively. Few studies used vasoactive compounds, and virtually all studies examined entry from the lumen and not from the perivascular space. We compared several mechanisms that govern arterial heparin deposition after administration to the perivascular and endovascular aspects of the calf carotid artery in vitro and the rabbit iliac artery in vivo. In the absence of transmural hydrostatic pressure gradients, heparin deposition following endovascular administration was unaffected by deendothelialization and was indistinguishable from perivascular delivery. Deposition in the former was enhanced by the addition of a pressure gradient and to a greater extent in denuded arteries, indicating that convection influences transport but is dampened by the endothelium. Neither the endothelium nor the adventitia pose significant resistances to heparin. Deposition in vivo was greater following endovascular hydrogel release than perivascular application from similar devices to native or denuded arteries. The loss of drug to extra-arterial microvessels exceeded the loss of drug to the lumen flow. These findings are essential for describing vascular pharmacokinetics and for implementing local pharmacotherapies.

Role of receptor-mediated endocytosis in the antiangiogenic effects of human T lymphoblastic cell-derived microparticles

2012 ◽  
Vol 302 (8) ◽  
pp. R941-R949 ◽  
Author(s):  
Chun Yang ◽  
Wei Xiong ◽  
Qian Qiu ◽  
Zuo Shao ◽  
David Hamel ◽  
...  
Keyword(s):  
Cell Growth ◽  
Protein Expression ◽  
Therapeutic Potential ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Vascular Density ◽  
Receptor Mediated Endocytosis

Microparticles possess therapeutic potential regarding angiogenesis. We have demonstrated the contribution of apoptotic human CEM T lymphocyte-derived microparticles (LMPs) as inhibitors of angiogenic responses in animal models of inflammation and tumor growth. In the present study, we characterized the antivascular endothelial growth factor (VEGF) effects of LMPs on pathological angiogenesis in an animal model of oxygen-induced retinopathy and explored the role of receptor-mediated endocytosis in the effects of LMPs on human retinal endothelial cells (HRECs). LMPs dramatically inhibited cell growth of HRECs, suppressed VEGF-induced cell migration in vitro experiments, and attenuated VEGF-induced retinal vascular leakage in vivo. Intravitreal injections of fluorescently labeled LMPs revealed accumulation of LMPs in retinal tissue, with more than 60% reductions of the vascular density in retinas of rats with oxygen-induced neovascularization. LMP uptake experiments demonstrated that the interaction between LMPs and HRECs is dependent on temperature. In addition, endocytosis is partially dependent on extracellular calcium. RNAi-mediated knockdown of low-density lipoprotein receptor (LDLR) reduced the uptake of LMPs and attenuated the inhibitory effects of LMPs on VEGF-A protein expression and HRECs cell growth. Intravitreal injection of lentivirus-mediated RNA interference reduced LDLR protein expression in retina by 53% and significantly blocked the antiangiogenic effects of LMPs on pathological vascularization. In summary, the potent antiangiogenic LMPs lead to a significant reduction of pathological retinal angiogenesis through modulation of VEGF signaling, whereas LDLR-mediated endocytosis plays a partial, but pivotal, role in the uptake of LMPs in HRECs.

scholarly journals Role of TNF-α in vascular dysfunction

2009 ◽  
Vol 116 (3) ◽  
pp. 219-230 ◽  
Author(s):  
Hanrui Zhang ◽  
Yoonjung Park ◽  
Junxi Wu ◽  
Xiu ping Chen ◽  
Sewon Lee ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Nuclear Factor Κb ◽  
Tnf Α ◽  
Density Lipoprotein Receptor

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-α plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-κB (nuclear factor κB) signalling play key roles in TNF-α expression through an increase in circulating and/or local vascular TNF-α production. The increase in TNF-α expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-α expression. The interaction between TNF-α and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-α in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.

scholarly journals Reductions of copper ion-mediated low-density lipoprotein (LDL) oxidations of trypsin inhibitors, the sweet potato root major proteins, and LDL binding capacities

2020 ◽  
Vol 61 (1) ◽  
Author(s):  
Yeh-Lin Lu ◽  
Chia-Jung Lee ◽  
Shyr-Yi Lin ◽  
Wen-Chi Hou
Keyword(s):  
Sweet Potato ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Trypsin Inhibitors ◽  
Water Soluble ◽  
Affinity Column ◽  
Low Density ◽  
Native Page

Abstract Background The root major proteins of sweet potato trypsin inhibitors (SPTIs) or named sporamin, estimated for 60 to 80% water-soluble proteins, exhibited many biological activities. The human low-density lipoprotein (LDL) showed to form in vivo complex with endogenous oxidized alpha-1-antitrypsin. Little is known concerning the interactions between SPTIs and LDL in vitro. Results The thiobarbituric-acid-reactive-substance (TBARS) assays were used to monitor 0.1 mM Cu2+-mediated low-density lipoprotein (LDL) oxidations during 24-h reactions with or without SPTIs additions. The protein stains in native PAGE gels were used to identify the bindings between native or reduced forms of SPTIs or soybean TIs and LDL, or oxidized LDL (oxLDL). It was found that the SPTIs additions showed to reduce LDL oxidations in the first 6-h and then gradually decreased the capacities of anti-LDL oxidations. The protein stains in native PAGE gels showed more intense LDL bands in the presence of SPTIs, and 0.5-h and 1-h reached the highest one. The SPTIs also bound to the oxLDL, and low pH condition (pH 2.0) might break the interactions revealed by HPLC. The LDL or oxLDL adsorbed onto self-prepared SPTIs-affinity column and some components were eluted by 0.2 M KCl (pH 2.0). The native or reduced SPTIs or soybean TIs showed different binding capacities toward LDL and oxLDL in vitro. Conclusion The SPTIs might be useful in developing functional foods as antioxidant and nutrient supplements, and the physiological roles of SPTIs-LDL and SPTIs-oxLDL complex in vivo will investigate further using animal models.

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