scholarly journals Electronegative LDL from Rabbits Fed with Atherogenic Diet Is Highly Proinflammatory

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Po-Yuan Chang ◽  
Jou-Hsiang Pai ◽  
Yu-Sheng Lai ◽  
Shao-Chun Lu
Keyword(s):  
Tumor Necrosis ◽  
Culture Medium ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Anion Exchange Chromatography ◽  
Atherogenic Diet ◽  
Exchange Chromatography ◽  
Necrosis Factor

Electronegative low-density lipoprotein (LDL(-)) has been found in the plasma of familial hypercholesterolemia and acute myocardial infarction and has been implicated in atherosclerosis and cardiovascular disease. However, less is known about the involvement of LDL(-) in atherosclerosis-related inflammation. This study aims at investigating the inducibility of LDL(-) by atherogenic diet in rabbits and at exploring the proinflammatory potential of the diet-induced LDL(-) in macrophages. Rabbits were fed with an atherogenic diet; LDL was isolated from plasma by NaBr density gradient ultracentrifugation and was then resolved into nLDL and LDL(-) by anion-exchange chromatography. Isolated nLDL and LDL(-) were directly used or incubated with 10 μM CuSO4 for 24 h to produce copper- (Cu-) ox-nLDL and Cu-ox-LDL(-). The effects of these LDLs on inflammation were evaluated in THP-1-derived macrophages. Macrophages were treated with nLDL, LDL(-), and extensively oxidized LDL (ox-LDL), then the levels of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α in a culture medium were determined by ELISA, and the levels of total and phosphorylated IκB, p65, p38, JNK, and ERK in cell lysates were determined by Western blotting. The LDL(-) induced significantly higher levels of IL-1β, IL-6, and TNF-α in the medium. The levels of phosphorylated/total IκB, p65, p38, JNK, and ERK were also upregulated by LDL(-). In contrast, nLDL, Cu-ox-nLDL, and Cu-ox-LDL(-) exhibited much less effect. Knockdown of lectin-type oxidized LDL receptor- (LOX-) 1 resulted in significant reduction in LDL(-)-induced IL-1β, IL-6, and TNF-α. In addition, these LDL(-) effects were also markedly attenuated by inhibition of NF-κB and ERK1/2. The data suggested that LDL(-) induced inflammation through LOX-1-, NF-κB-, and ERK1/2-dependent pathways. Taken together, our results show that rabbits fed with atherogenic diet produce a highly proinflammatory LDL(-) that is more potent in inducing inflammation than nLDL and extensively oxidize LDL in macrophages. The results thus provide a novel link between diet-induced hypercholesterolemia and inflammation.

scholarly journals Tumor necrosis factor induces cholesterol accumulation in human arterial endothelial cells through LDL receptor surface redistribution

2020 ◽  
Author(s):  
Emmanuel Ugochukwu Okoro
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Oxidized Ldl ◽  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Human Aortic Endothelial Cell ◽  
Surface Binding ◽  
Necrosis Factor Alpha ◽  
Necrosis Factor

ABSTRACTTumor necrosis factor alpha (TNFα) and low density lipoprotein (LDL) are important modulators of the atherosclerotic process. Here, the effect of TNFα on confluent primary human aortic endothelial cell (pHAEC) LDL-derived lipids and trafficking were investigated. TNFα promoted up to 2 folds increase in cellular cholesterol and could induce a massive increase in the non-hydrolysable tracer, Dil, by over 200 folds. The lipid increase was associated with increased 125I-LDL surface binding. Further, Dil-LDL cellular association was blocked by excess unlabeled LDL, but not oxidized LDL (oxLDL). Moreover, TNFα-induced Dil and cholesterol increase were enhanced by the endosomal pH-raising agent, chloroquine. Internalization of Dil-LDL was reduced by the scavenger receptor B1 (SR-B1) antagonist, BLT-1, and the LDLR family antagonist, proprotein convertase subtilisin/kexin type 9 (PCSK9), but not receptor associated protein (R AP). Additionally, surface accessible LDLR was higher in TNFα-treated cells by about 30 folds, without a significant change in total LDLR. Correspondingly, specific LDLR antibody blocked Dil-LDL internalization to undetectable levels, and Dil-apoE3-VLDL by 94%, but had no effect on Dil-HDL3 internalization. TNFα did not increase Dil-HDL3 cellular association. Further, ACAT inhibitor reduced cholesteryl esters, but not the total cholesterol increase induced by TNFα. On pHAECs grown on transwell inserts, TNFα did not enhance apical (AP) to basolateral (BL) LDL cholesterol or Dil release. It is concluded that TNFα induces LDLR surface localization and that LDLR does not promote AP to BL LDL transport across pHAECs.

Glycation and HMG-CoA Reductase Inhibitors: Implication in Diabetes and Associated Complications

2019 ◽  
Vol 15 (3) ◽  
pp. 213-223 ◽  
Author(s):  
Rabia Nabi ◽  
Sahir Sultan Alvi ◽  
Mohd. Saeed ◽  
Saheem Ahmad ◽  
Mohammad Salman Khan
Keyword(s):  
Oxidized Ldl ◽  
Advanced Glycation Endproducts ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Protective Role ◽  
Therapeutic Effects ◽  
Hmg Coa Reductase ◽  
Toxicological Effects ◽  
Coa Reductase

Introduction: Diabetes Mellitus (DM) acts as an absolute mediator of cardiovascular risk, prompting the prolonged occurrence, size and intricacy of atherosclerotic plaques via enhanced Advanced Glycation Endproducts (AGEs) formation. Moreover, hyperglycemia is associated with enhanced glyco-oxidized and oxidized Low-Density Lipoprotein (LDL) possessing greater atherogenicity and decreased the ability to regulate HMG-CoA reductase (HMG-R). Although aminoguanidine (AG) prevents the AGE-induced protein cross-linking due to its anti-glycation potential, it exerts several unusual pharmaco-toxicological effects thus restraining its desirable therapeutic effects. HMG-R inhibitors/statins exhibit a variety of beneficial impacts in addition to the cholesterol-lowering effects. Objective: Inhibition of AGEs interaction with receptor for AGEs (RAGE) and glyco-oxidized-LDL by HMG-R inhibitors could decrease LDL uptake by LDL-receptor (LDL-R), regulate cholesterol synthesis via HMG-R, decrease oxidative and inflammatory stress to improve the diabetes-associated complications. Conclusion: Current article appraises the pathological AGE-RAGE concerns in diabetes and its associated complications, mainly focusing on the phenomenon of both circulatory AGEs and those accumulating in tissues in diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy, discussing the potential protective role of HMG-R inhibitors against diabetic complications.

Abstract 16069: Low-Density Lipoprotein of Systemic Lupus Erythematosus Patients Contains Lysophosphatidylcholine-Rich Lipid That Induces Overexpression of CX3CL1 in Endothelial Cells

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Hua-Chen Chan ◽  
Liang-Yin Ke ◽  
Hsiu-Chuan Chan ◽  
Hung Su ◽  
An-Sheng Lee ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Cardiovascular Disease ◽  
Endothelial Cells ◽  
Lupus Erythematosus ◽  
Low Density Lipoprotein ◽  
Chemical Properties ◽  
Density Lipoprotein ◽  
Anion Exchange Chromatography ◽  
Exchange Chromatography ◽  
Systemic Lupus

Background: Patients with systemic lupus erythematosus (SLE) are twice more likely to develop cardiovascular disease than the general population, even though their plasma LDL cholesterol (LDL-C) levels are usually not elevated. To delineate the mechanisms, we examined the chemical properties of their LDL. Methods and Results: LDL isolated from SLE patients (LDL-C, 105±33 mg/dL; n=24) exhibited greater mobility in agarose gel electrophoresis than LDL of healthy control subjects (LDL-C, 121±25 mg/dL; n=24), secondary to an increased distribution of L5 (2.30±1.3% vs. 0.7±0.3%; P <0.0001), the most electronegative subfraction of LDL identified by anion-exchange chromatography, in total LDL. CX3CL1 is a membrane-bound chemokine expressed in injured endothelial cells (ECs). CD16 + monocytes are CX3CR1-expressing cells that recognize CX3CL1. Compared with control, SLE patients had a twofold ( P <0.001) increase in CX3CL1 and a threefold ( P <0.0001) increase in CD16 + monocytes in the plasma. Moreover, there was a positive correlation between the CX3CL1 and L5 levels (R=0.45; P <0.018). MALDI/TOF mass spectrometry of the lipid extracted from SLE-LDL revealed a shift from phosphatidylcholines (PCs) to lyso-PCs (LPCs), including m/ z 496.33, 524.36, 537.01, 550.94, when compared with the lipid of control LDL (Figure). The shift was especially prominent in L5. Exposing human aortic ECs to L5 but not normal LDL resulted in a fivefold ( P <0.0001) increase in CX3CL1 expression with concomitant apoptosis. These effects of L5 were significantly attenuated by blocking the platelet-activating receptor, confirming the role of phospholipids in L5’s bioactivity. Conclusions: The increased distribution of LPC-rich electronegative LDL, which induces CX3CL1-CX3CR1 interactions between vascular cells, may contribute to the increased cardiovascular disease prevalence in SLE in the absence of LDL-C elevation.

scholarly journals Oxidized LDL but not angiotensin II induces the interaction between LOX-1 and AT1 receptors

2020 ◽  
Author(s):  
Li Lin ◽  
Ning Zhou ◽  
Le Kang ◽  
Qi Wang ◽  
Jian Wu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Direct Interaction ◽  
Cardiomyocyte Hypertrophy ◽  
Oxidized Low Density Lipoprotein ◽  
Protein Activation

Oxidized low-density lipoprotein (Ox-LDL) can induce cardiac hypertrophy, but the mechanism is still unclear. Here we elucidate the role of angiotensin II (AngII) receptor (AT1-R) in Ox-LDL-induced cardiomycyte hypertrophy. Inhibition of Ox-LDL receptor LOX-1 and AT1-R rather than AngII abolished Ox-LDL-induced hypertrophic responses. Similar results were obtained from the heart of mice lacking endogenous Ang II and their cardiomyocytes. Ox-LDL but not AngII induced binding of LOX-1 to AT1-R, and the inhibition of LOX-1 or AT1-R rather than AngII abolished the association of these two receptors. Ox-LDL-induced ERKs phosphorylation in LOX-1 and AT1-R-overexpression cells and the binding of both receptors were suppressed by the mutants of LOX-1 (Lys266Ala/Lys267Ala) or AT1-R (Glu257Ala), however, the AT1-R mutant lacking Gq protein-coupling ability only abolished the ERKs phosphorylation. The phosphorylation of ERKs induced by Ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by Gq protein inhibitor but not by Jak2, Rac1 and RhoA inhibitors. Therefore, the direct interaction between LOX-1 and AT1-R and the downstream Gq protein activation are important mechanisms for Ox-LDL- but not AngII-induced cardiomyocyte hypertrophy

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease

2020 ◽  
Author(s):  
Alexander Akhmedov ◽  
Tatsuya Sawamura ◽  
Chu-Huang Chen ◽  
Simon Kraler ◽  
Daria Vdovenko ◽  
...  
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Basic Research ◽  
Plaque Formation ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Atheromatous Plaques

Abstract Cardiovascular diseases (CVDs), specifically lipid-driven atherosclerotic CVDs, remain the number one cause of death worldwide. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a scavenger receptor that promotes endothelial dysfunction by inducing pro-atherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke. In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation. LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs; therefore, understanding the molecular structure and function of LOX-1 is of critical importance. In this review, we highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs. We describe recent findings from basic research, delineate their translational value, and discuss the potential of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs.

PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1

2019 ◽  
Vol 116 (5) ◽  
pp. 908-915 ◽  
Author(s):  
Zufeng Ding ◽  
Naga Venkata K Pothineni ◽  
Akshay Goel ◽  
Thomas F Lüscher ◽  
Jawahar L Mehta
Keyword(s):  
Inflammatory Cytokines ◽  
Ldl Cholesterol ◽  
Vascular Endothelial Cells ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Prevention Of Atherosclerosis ◽  
Pro Inflammatory Cytokines

Abstract PCSK9 degrades low-density lipoprotein cholesterol (LDL) receptors and subsequently increases serum LDL cholesterol. Clinical trials show that inhibition of PCSK9 efficiently lowers LDL cholesterol levels and reduces cardiovascular events. PCSK9 inhibitors also reduce the extent of atherosclerosis. Recent studies show that PCSK9 is secreted by vascular endothelial cells, smooth muscle cells, and macrophages. PCSK9 induces secretion of pro-inflammatory cytokines in macrophages, liver cells, and in a variety of tissues. PCSK9 regulates toll-like receptor 4 expression and NF-κB activation as well as development of apoptosis and autophagy. PCSK9 also interacts with oxidized-LDL receptor-1 (LOX-1) in a mutually facilitative fashion. These observations suggest that PCSK9 is inter-twined with inflammation with implications in atherosclerosis and its major consequence—myocardial ischaemia. This relationship provides a basis for the use of PCSK9 inhibitors in prevention of atherosclerosis and related clinical events.

scholarly journals Significance of Soluble Lectin-Like Oxidized LDL Receptor-1 Levels in Systemic and Coronary Circulation in Acute Coronary Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Tomofumi Misaka ◽  
Satoshi Suzuki ◽  
Nobuo Sakamoto ◽  
Takayoshi Yamaki ◽  
Koichi Sugimoto ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Coronary Circulation ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
High Sensitivity ◽  
Coronary Intervention ◽  
Coronary Syndrome ◽  
Density Lipoprotein Receptor

Background.Soluble lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) level is a novel biomarker for diagnosis of acute coronary syndrome (ACS); however, this level in the coronary circulation has yet to be examined.Methods.Twenty-seven consecutive patients with ACS and 40 patients with effort angina pectoris (EAP) undergoing percutaneous coronary intervention (PCI) had levels of soluble LOX-1 and LOX-1 index measured in paired blood samples from aorta (Ao) and coronary sinus (CS) just prior to the PCI.Results.We found positive correlations between soluble LOX-1 levels in the Ao and CS in both ACS and EAP patients (P<0.01, for both). The soluble LOX-1 levels in the Ao and CS were higher in ACS than in EAP patients (P<0.01, for both). The levels of soluble LOX-1 and LOX-1 index of the CS were significantly greater than those of the Ao in both ACS and EAP patients (P<0.01, for both). Receiver operating characteristic curves for ACS detection demonstrated high sensitivity and specificity for the soluble LOX-1 and LOX-1 index with no differences between the Ao and CS.Conclusions.The present study showed that circulating soluble LOX-1 originates from coronary circulation and soluble LOX-1 and LOX-1 index are useful biomarkers for ACS.

scholarly journals Infectivity of Hepatitis C Virus Is Influenced by Association with Apolipoprotein E Isoforms

2010 ◽  
Vol 84 (22) ◽  
pp. 12048-12057 ◽  
Author(s):  
Takayuki Hishiki ◽  
Yuko Shimizu ◽  
Reiri Tobita ◽  
Kazuo Sugiyama ◽  
Kazuya Ogawa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Apolipoprotein E ◽  
Culture Medium ◽  
Low Density Lipoprotein ◽  
Ectopic Expression ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Virus Production ◽  
Low Density

ABSTRACT Hepatitis C virus (HCV) is a causative agent of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV in circulating blood associates with lipoproteins such as very low density lipoprotein (VLDL) and low-density lipoprotein (LDL). Although these associations suggest that lipoproteins are important for HCV infectivity, the roles of lipoproteins in HCV production and infectivity are not fully understood. To clarify the roles of lipoprotein in the HCV life cycle, we analyzed the effect of apolipoprotein E (ApoE), a component of lipoprotein, on virus production and infectivity. The production of infectious HCV was significantly reduced by the knockdown of ApoE. When an ApoE mutant that fails to be secreted into the culture medium was used, the amount of infectious HCV in the culture medium was dramatically reduced; the infectious HCV accumulated inside these cells, suggesting that infectious HCV must associate with ApoE prior to virus release. We performed rescue experiments in which ApoE isoforms were ectopically expressed in cells depleted of endogenous ApoE. The ectopic expression of the ApoE2 isoform, which has low affinity for the LDL receptor (LDLR), resulted in poor recovery of infectious HCV, whereas the expression of other isoforms, ApoE3 and ApoE4, rescued the production of infectious virus, raising it to an almost normal level. Furthermore, we found that the infectivity of HCV required both the LDLR and scavenger receptor class B, member I (SR-BI), ligands for ApoE. These findings indicate that ApoE is an essential apolipoprotein for HCV infectivity.

scholarly journals Role of Lectin-Like Oxidized Low Density Lipoprotein-1 in Fetoplacental Vascular Dysfunction in Preeclampsia

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Felipe A. Zuniga ◽  
Valeska Ormazabal ◽  
Nicolas Gutierrez ◽  
Valeria Aguilera ◽  
Claudia Radojkovic ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Dysfunction ◽  
Pathological Condition ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Fetal Loss ◽  
Density Lipoprotein ◽  
Placental Tissue

The bioavailability of nitric oxide (NO) represents a key marker in vascular health. A decrease in NO induces a pathological condition denominated endothelial dysfunction, syndrome observed in different pathologies, such as obesity, diabetes, kidney disease, cardiovascular disease, and preeclampsia (PE). PE is one of the major risks for maternal death and fetal loss. Recent studies suggest that the placenta of pregnant women with PE express high levels of lectin-like oxidized LDL receptor-1 (LOX-1), which induces endothelial dysfunction by increasing reactive oxygen species (ROS) and decreasing intracellular NO. Besides LOX-1 activation induces changes in migration and apoptosis of syncytiotrophoblast cells. However, the role of this receptor in placental tissue is still unknown. In this review we will describes the physiological roles of LOX-1 in normal placenta development and the potential involvement of this receptor in the pathophysiology of PE.

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