Oxidized cholesterol exacerbates toll-like receptor 4 expression and activity in the hearts of rats with myocardial infarction

Introduction: The present study examined the effects of high cholesterol and high oxidized-cholesterol diets on the myocardial expression of TLR4 and pro-inflammatory cytokine in rats.<br /> Methods: Male Wistar rats were allocated into 6 groups and fed with a normal diet, cholesterol, and oxidized-cholesterol rich diets with or without isoproterenol-induced myocardial infarction. TLR4 and MyD 88 expression and levels tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were measured in the heart and serum. <br /> Results: Oxidized cholesterol-fed animals had higher serum levels of oxidized low-density lipoprotein (LDL) (263 ± 13 ng/dL) than the cholesterol-fed animals (98 ± 8 ng/dL; P < 0.001). A high level of oxidized-LDL caused fibrotic cell formation and enhanced neutrophil infiltration in the absence of MI. Both cholesterol and oxidized-cholesterol upregulated TLR4 mRNA expression and increased TNF-α and IL-6 production in the hearts of rats with MI. In rats fed with oxidized-cholesterol the serum and myocardial levels of TNF-α (653 ± 42 pg/mL, 1375 ± 121 pg/100 mg, respectively) were higher than MI group (358±24 pg/mL, P < 0.001 and 885 ± 56 pg/100 mg, P < 0.01). A significant correlation was seen between TLR4 expression and infarct size.<br /> Conclusion: These findings suggest that cardiac TLR4 is preferentially upregulated by oxidized cholesterol in rats. Oxidized cholesterol may have a critical role in cardiac toxicity in the absence of pathological conditions.

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Streptokinase Promotes Development of Dipeptidyl Peptidase IV (CD26) Autoantibodies after Fibrinolytic Therapy in Myocardial Infarction Patients

Clinical and Vaccine Immunology ◽

10.1128/cdli.9.6.1253-1259.2002 ◽

2002 ◽

Vol 9 (6) ◽

pp. 1253-1259 ◽

Cited By ~ 1

Author(s):

Miguel Cuchacovich ◽

Héctor Gatica ◽

Paula Vial ◽

Jorge Yovanovich ◽

Salvatore V. Pizzo ◽

...

Keyword(s):

Myocardial Infarction ◽

Lupus Erythematosus ◽

Inflammatory Diseases ◽

Critical Role ◽

Serum Levels ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Necrosis Factor Alpha ◽

Dpp Iv ◽

Tnf Α

ABSTRACT Dipeptidyl peptidase IV (DPP IV) (CD26) plays a critical role in the modulation and expression of autoimmune and inflammatory diseases. We recently reported that sera from patients with rheumatoid arthritis and systemic lupus erythematosus contained low levels of DPP IV and high titers of anti-DPP IV autoantibodies of the immunoglobulin A (IgA) and IgG classes and found a correlation between the low circulating levels of DPP IV and the high titers of anti-DPP IV autoantibodies of the IgA class. Since streptokinase (SK) is a potent immunogen and binds to DPP IV, we speculated that patients with autoimmune diseases showed higher DPP IV autoantibody levels than healthy controls as a consequence of an abnormal immune stimulation triggered by SK released during streptococcal infections. We assessed this hypothesis in a group of patients suffering from acute myocardial infarction, without a chronic autoimmune disease, who received SK as part of therapeutic thrombolysis. Concomitant with the appearance of anti-SK antibodies, these patients developed anti-DPP IV autoantibodies. These autoantibodies bind to DPP IV in the region which is also recognized by SK, suggesting that an SK-induced immune response is responsible for the appearance of DPP IV autoantibodies. Furthermore, we determined a correlation between high titers of DPP IV autoantibodies and an augmented clearance of the enzyme from the circulation. Serum levels of the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) increased significantly after 30 days of SK administration, while the levels of soluble IL-2 receptor remained unchanged during the same period, suggesting a correlation between the lower levels of circulating DPP IV and higher levels of TNF-α and IL-6 in serum in these patients.

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Oral Mucosal Endotoxin Tolerance Induction in Chronic Periodontitis

Infection and Immunity ◽

10.1128/iai.73.2.687-694.2005 ◽

2005 ◽

Vol 73 (2) ◽

pp. 687-694 ◽

Cited By ~ 107

Author(s):

Manoj Muthukuru ◽

Ravi Jotwani ◽

Christopher W. Cutler

Keyword(s):

Immune Response ◽

Oral Mucosa ◽

Chronic Periodontitis ◽

Intracellular Signaling ◽

Inflammatory Responses ◽

Endotoxin Tolerance ◽

Necrosis Factor Alpha ◽

Initial Stimulus ◽

Tlr4 Mrna ◽

Tnf Α

ABSTRACT The oral mucosa is exposed to a high density and diversity of gram-positive and gram-negative bacteria, but very little is known about how immune homeostasis is maintained in this environment, particularly in the inflammatory disease chronic periodontitis (CP). The cells of the innate immune response recognize bacterial structures via the Toll-like receptors (TLR). This activates intracellular signaling and transcription of proteins essential for the induction of an adaptive immune response; however, if unregulated, it can lead to destructive inflammatory responses. Using single-immunoenzyme labeling, we show that the human oral mucosa (gingiva) is infiltrated by large numbers of TLR2+ and TLR4+ cells and that their numbers increase significantly in CP, relative to health (P < 0.05, Student's t test). We also show that the numbers of TLR2+ but not TLR4+ cells increase linearly with inflammation (r 2 = 0.33, P < 0.05). Double-immunofluorescence analysis confirms that TLR2 is coexpressed by monocytes (MC)/macrophages (mφ) in situ. Further analysis of gingival tissues by quantitative real-time PCR, however, indicates that despite a threefold increase in the expression of interleukin-1β (IL-1β) mRNA during CP, there is significant (30-fold) downregulation of TLR2 mRNA (P < 0.05, Student's t test). Also showing similar trends are the levels of TLR4 (ninefold reduction), TLR5 (twofold reduction), and MD-2 (sevenfold reduction) mRNA in CP patients compared to healthy persons, while the level of CD14 was unchanged. In vitro studies with human MC indicate that MC respond to an initial stimulus of lipopolysaccharide (LPS) from Porphyromonas gingivalis (PgLPS) or Escherichia coli (EcLPS) by upregulation of TLR2 and TLR4 mRNA and protein; moreover, IL-1β mRNA is induced and tumor necrosis factor alpha (TNF-α), IL-10, IL-6, and IL-8 proteins are secreted. However, restimulation of MC with either PgLPS or EcLPS downregulates TLR2 and TLR4 mRNA and protein and IL-1β mRNA and induces a ca. 10-fold reduction in TNF-α secretion, suggesting the induction of endotoxin tolerance by either LPS. Less susceptible to tolerance than TNF-α were IL-6, IL-10, and IL-8. These studies suggest that certain components of the innate oral mucosal immune response, most notably TLRs and inflammatory cytokines, may become tolerized during sustained exposure to bacterial structures such as LPS and that this may be one mechanism used in the oral mucosa to attempt to regulate local immune responses.

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Anti-Atherosclerotic Activity of (3R)-5-Hydroxymellein from an Endophytic Fungus Neofusicoccum parvum JS-0968 Derived from Vitex rotundifolia through the Inhibition of Lipoproteins Oxidation and Foam Cell Formation

Biomolecules ◽

10.3390/biom10050715 ◽

2020 ◽

Vol 10 (5) ◽

pp. 715

Author(s):

Jae-Yong Kim ◽

Soonok Kim ◽

Sang Hee Shim

Keyword(s):

Conformational Changes ◽

Endophytic Fungus ◽

Foam Cell ◽

Oxidized Ldl ◽

Cell Formation ◽

Density Lipoprotein ◽

Ldl Oxidation ◽

Foam Cell Formation ◽

Macrophage Foam Cell ◽

Neofusicoccum Parvum

An endophytic fungus, Neofusicoccum parvum JS-0968, was isolated from a plant, Vitex rotundifolia. The chemical investigation of its cultures led to the isolation of a secondary metabolite, (3R)-5-hydroxymellein. It has been reported to have antifungal, antibacterial, and antioxidant activity, but there have been no previous reports on the effects of (3R)-5-hydroxymellein on atherosclerosis. The oxidation of lipoproteins and foam cell formation have been known to be significant in the development of atherosclerosis. Therefore, we investigated the inhibitory effects of (3R)-5-hydroxymellein on atherosclerosis through low-density lipoprotein (LDL) and high-density lipoprotein (HDL) oxidation and macrophage foam cell formation. LDL and HDL oxidation were determined by measuring the production of conjugated dienes and malondialdehyde, the amount of hyperchromicity and carbonyl content, conformational changes, and anti-LDL oxidation. In addition, the inhibition of foam cell formation was measured by Oil red O staining. As a result, (3R)-5-hydroxymellein suppressed the oxidation of LDL and HDL through the inhibition of lipid peroxidation, the decrease of negative charges, the reduction of hyperchromicity and carbonyl contents, and the prevention of apolipoprotein A-I (ApoA-I) aggregation and apoB-100 fragmentation. Furthermore, (3R)-5-hydroxymellein significantly reduced foam cell formation induced by oxidized LDL (oxLDL). Taken together, our data show that (3R)-5-hydroxymellein could be a potential preventive agent for atherosclerosis via obvious anti-LDL and HDL oxidation and the inhibition of foam cell formation.

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Cellular Uptake and Clearance of Oxidatively-modified Apolipoprotein E3 by Cerebral Cortex Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20184582 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4582 ◽

Cited By ~ 1

Author(s):

Siobanth Cruz ◽

Vasanthy Narayanaswami

Keyword(s):

Endothelial Cells ◽

Cellular Uptake ◽

Hot Spot ◽

Oxidized Ldl ◽

Critical Role ◽

Density Lipoprotein ◽

Oxidative Modification ◽

Alternative Mechanism ◽

Type I ◽

Western Blots

Apolipoprotein E3 (apoE3) plays a critical role in the metabolism of lipoproteins and lowers plasma lipid levels by serving as a ligand for the low-density lipoprotein receptor (LDLr) family of proteins and by promoting macrophage cholesterol efflux. The current study examines the effect of acrolein (an endogenously generated metabolite and an environmental pollutant) modification on the structure and function of apoE3. Acrolein modification was confirmed in Western blots by reactivity with acrolein–lysine-specific antibody and by the presence of oligomeric species due to cross-linking. LC-MS/MS analysis revealed modification of 10 out of 12 lysines in apoE3, with Nε-(3-methylpyridinium)-lysine being the predominant form of modification, and Lys75 being a ‘hot spot’ in terms of susceptibility to oxidation. Circular dichroism spectroscopy showed no major change in overall secondary structure compared to unmodified apoE3. Reconstituted high density lipoprotein (HDL) bearing acrolein modified apoE3 showed loss of binding to soluble LDLr; however, incubation with mouse endothelioma bEnd.3 cells showed that it was internalized. Incubation with excess LDL did not abolish cellular uptake of acrolein modified apoE3, suggesting alternative mechanism(s) not involving LDLr. Incubation with anti-CD36 antibody did not show a decrease in internalization while incubation with anti- lectin-like oxidized LDL receptor 1 (LOX1) showed partial internalization. However, incubation with anti-scavenger receptor class B type I (SRB1) antibody abolished internalization of acrolein modified apoE3. Taken together, our studies suggest that acrolein modification of apoE3 at lysine residues leads to increase in net negative charge, and as a consequence, results in clearance by LOX1 and SRB1 on endothelial cells. Overall, oxidative modification of apoE3 likely impairs its role in regulating plasma cholesterol homeostasis, eventually leading to lipid disorders.

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Oxidized LDL Modify the Human Adipocyte Phenotype to an Insulin Resistant, Proinflamatory and Proapoptotic Profile

Biomolecules ◽

10.3390/biom10040534 ◽

2020 ◽

Vol 10 (4) ◽

pp. 534 ◽

Cited By ~ 3

Author(s):

Concepción Santiago-Fernández ◽

Flores Martin-Reyes ◽

Mónica Tome ◽

Luis Ocaña-Wilhelmi ◽

Jose Rivas-Becerra ◽

...

Keyword(s):

Glucose Uptake ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Morbidly Obese ◽

Insulin Resistant ◽

Tnf Α ◽

Obese Subjects ◽

Factor Α ◽

Visceral Adipose

Little information exists in humans on the regulation that oxidized low-density lipoprotein (oxLDL) exerts on adipocyte metabolism, which is associated with obesity and type 2 diabetes. The aim was to analyze the oxLDL effects on adipocytokine secretion and scavenger receptors (SRs) and cell death markers in human visceral adipocytes. Human differentiated adipocytes from visceral adipose tissue from non-obese and morbidly obese subjects were incubated with increasing oxLDL concentrations. mRNA expression of SRs, markers of apoptosis and autophagy, secretion of adipocytokines, and glucose uptake were analyzed. In non-obese and in morbidly obese subjects, oxLDL produced a decrease in insulin-induced glucose uptake, a significant dose-dependent increase in tumor necrosis factor-α (TNF-α), IL-6, and adiponectin secretion, and a decrease in leptin secretion. OxLDL produced a significant increase of Lox-1 and a decrease in Cxcl16 and Cl-p1 expression. The expression of Bnip3 (marker of apoptosis, necrosis and autophagy) was significantly increased and Bcl2 (antiapoptotic marker) was decreased. OxLDL could sensitize adipocytes to a lower insulin-induced glucose uptake, a more proinflammatory phenotype, and could modify the gene expression involved in apoptosis, autophagy, necrosis, and mitophagy. OxLDL can upregulate Lox-1, and this could lead to a possible amplification of proinflammatory and proapoptotic effects of oxLDL.

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Are N-acetylcysteine and adalimumab effective for non-alcoholic steatohepatitis?

Gastroenterology Insights ◽

10.4081/gi.2016.6227 ◽

2016 ◽

Vol 7 (1) ◽

Author(s):

Mustafa Yalçın ◽

Muhammed Ali Kıyak ◽

Mesut Akarsu ◽

Aslı Çelik ◽

Göksel Bengi ◽

...

Keyword(s):

Oxidative Stress ◽

Treatment Options ◽

Diet Group ◽

Normal Diet ◽

The Other ◽

Albino Rats ◽

Necrosis Factor Alpha ◽

Alcoholic Steatohepatitis ◽

Tnf Α ◽

And Oxidative Stress

Due to the lack of effective medical treatment for non-alcoholic steatohepatitis (NASH), we aimed to evaluate new treatment options. In particular, our goal was to investigate and compare the effects of N-acetylcysteine (NAC) and Adalimumab treatment on tumor necrosis factor alpha (TNF-α) and oxidative stress during the development of NASH in a rat model of the disease. Our study included a total of 35 female Wistar albino rats that were divided into 5 groups of 7 each, and evaluated over a 6 week period. One group received a normal diet, while the other four groups received a methionine and choline deficient (MCD) diet. One of the groups receiving the MCD diet did not take any medicine, while the other three were administered NAC, adalimumab, or a NAC/adalimumab combination therapy. NASH was successfully established in the MCD diet group. Levels of TNF-α were effectively suppressed in the three groups that received therapy. Even though adalimumab significantly enhanced suppression of TNF-α, the NASH score was suppressed to a more statistically significant extent in the groups receiving NAC. Our study showed that TNF-α and oxidative stress play an important role in NASH pathogenesis. The antioxidant agent, NAC, was found to be superior to the anti-TNF agent, Adalimumab, in the improvement of total NASH score. Although these drugs did not prevent the development of NASH, it was shown that they mildly reverse the NASH histopathology score, suggesting improvement of and overall liver function.

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The immune system mediates blood-brain barrier damage; possible implications for pathophysiology of neuropsychiatric illnesses

Acta Neuropsychiatrica ◽

10.1017/s0924270800037315 ◽

1995 ◽

Vol 7 (4) ◽

pp. 114-121 ◽

Cited By ~ 9

Author(s):

Y.D. Van Der Werf ◽

M.J.L. De Jongste ◽

G.J. Ter Horst

Keyword(s):

Myocardial Infarction ◽

Immune System ◽

Blood Brain Barrier ◽

Immune Activation ◽

Inflammatory Cytokine ◽

Brain Barrier ◽

Necrosis Factor Alpha ◽

Blood Brain ◽

Tnf Α ◽

The Brain

SummaryIn this investigation the effects of immune activation on the brain are characterized. In order to study this, we used a model for chronic immune activation, the myocardial infarction, and intravenous injections with the pro-inflammatory cytokine Tumour Necrosis Factor alpha (TNF-α). The incentive for this study is the observation that myocardial infarction is accompanied by behavioural and neuronal abnormalities. The effects of myocardial infarction on the brain and its functioning are widespread. In order to examine the mechanism through which this interaction occurs, a group of rats underwent an experimentally induced myocardial infarction whereafter immunohistochemistry was performed on slices of the brain. This experiment revealed regional serum protein extravasation, pointing to leakage of the blood-brain barrier. This process occurred in certain cortical, subcortical and hindbrain areas in discrete patches. The leakage was co-localized with the expression of the immune activation marker ICAM-1. A second group of rats was therefore injected with TNF-α, a major pro-inflammatory cytokine, to assess the involvement of the immune system in the effects shown. This procedure rendered the same results. It is concluded that myocardial infarction may interfere with the integrity of the blood-brain barrier and possibly with brain functioning through activation of the immune system. The relevance for pathophysiological processes is discussed.

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Serum irisin level in myocardial infarction patients with or without heart failure

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0736 ◽

2019 ◽

Vol 97 (10) ◽

pp. 932-938 ◽

Cited By ~ 4

Author(s):

Nashwa A. Abd El-Mottaleb ◽

Heba M. Galal ◽

Khaled M. El Maghraby ◽

Aml I. Gadallah

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Troponin I ◽

Density Lipoprotein ◽

Left Ventricular ◽

Lipoprotein Cholesterol ◽

Cholesterol Concentration ◽

Left Ventricular Ejection ◽

Cardiac Markers ◽

Tnf Α

This study aimed to assess serum irisin level in myocardial infarction (MI) with or without heart failure (HF) and the possible relation between irisin and cardiac markers, tumor necrosis factor-α (TNF-α) and lipid profile. Eighty-six subjects were included (33 patients had MI, 33 patients had MI with HF, and 20 controls). Body mass index (BMI), waist/hip ratio (WHR), systolic and diastolic blood pressure (SBP and DBP), heart rate, and left ventricular ejection fraction (LVEF) were measured. Blood samples were withdrawn on admission for measuring irisin, cardiac markers, TNF-α, total cholesterol (TC), triglycerides (TGs), low-density lipoprotein-cholesterol concentration (LDL-C), and high-density lipoprotein-cholesterol concentration (HDL-C). Patients with MI and HF had reduced serum irisin, LVEF, and HDL-C and higher levels of BMI, WHR, SBP, DBP, troponin-I, creatine kinase-MB (CK-MB), TNF-α, TC, TGs, and LDL-C compared with control. Negative correlations were observed between irisin and BMI, WHR, SBP, DBP, troponin-I, CK-MB, TNF-α, TC, TGs, and LDL-C. However, positive association was noticed between irisin and LVEF and HDL-C. Irisin might be a useful biomarker in diagnosis of MI with or without HF. It could have anti-inflammatory and hypolipidemic effects. Further studies are needed to elucidate the role of irisin as a promising prophylactic or therapeutic agent in cardiovascular diseases.

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EXTRAVASCULAR INJURY CAUSES FOAM CELL FORMATION, ACCUMULATION OF CHOLESTEROL (C) and CHOLESTEROL ESTER (CE) IN THE CAROTID ARTERY

10.1055/s-0038-1643414 ◽

1987 ◽

Author(s):

D C Hassall ◽

R F G Booth ◽

A C Honey ◽

J F Martin

Keyword(s):

Carotid Artery ◽

Histological Analysis ◽

Foam Cell ◽

Cell Formation ◽

Density Lipoprotein ◽

Distal Region ◽

Normal Diet ◽

Foam Cell Formation ◽

High Cholesterol ◽

Arterial Tissue

In atherosclerotic arterial tissue, cholesterol is delivered to smooth muscle cells by low-density lipoprotein (LDL) and to macrophages via modified LDL. The reasons for accumulation of excess lipid are unknown although increased uptake of C and CE occurs in regions of arterial de-endothelialisation. We now report that the positioning of a silastic collar containing saline around the outside of arteries induces accumulation of C and CE within those tissues. 9 rabbits were separated into 3 groups, each group was fed a normal laboratory chow, 2 groups were supplemented with lg/day cholesterol; these rabbits were used for C and CE determinations. Three parallel groups of rabbits were set up for histological analysis. At day O, under anaesthesia, a silastic collar was* placed around the left carotid artery. The collar was filled with saline and carefully sealed without causing constriction of the vessel. The vessels were replaced and the animals allowed to recover. After 14 days the carotids from animals for C and CE determination were rapidly removed and divided up into a region from the middle of the collar, a region proximal to the collar and a distal region. The tissues were freeze clamped in liquid nitrogen and lipids extracted with C and CE determined for each region. The carotids for histological analysis were perfuse-fixed in situ and similarly subdivided.We conclude 1) Animals fed high cholesterol accumulate more C than CE within arterial tissue, furthermore this accumulation is greater than in animals fed a normal diet 2) In both normal diet and high cholesterol fed animals an enhanced accumulation of C + CE occurs within arteries with a collar 3) CE appears to be preferentially accumulated within the collar region.

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Lipoproteins in heart disease

Perfusion ◽

10.1177/026765919601100407 ◽

1996 ◽

Vol 11 (4) ◽

pp. 338-345 ◽

Cited By ~ 2

Author(s):

Annette Basile-Borgia ◽

John H Abel

Keyword(s):

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Critical Role ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Acute Phase Reactant ◽

Essential Elements ◽

Current Data ◽

Atherosclerotic Cardiovascular Disease ◽

Key Steps

Most lipids are carried in the circulation by lipoproteins. Liproproteins and their associated proteins, called apolipoproteins, are currently being studied in an effort to further our understanding of atherosclerotic cardiovascular disease. Lipoprotein assembly, secretion, transportation, modification and clearance are essential elements of healthy lipid metabolism. When one or more of these key steps becomes altered, various disease states are induced. Current data suggest that lipoprotein(a), a low density lipoprotein (LDL)-like particle, is an acute phase reactant that plays a critical role in the modulation of fibrinolysis. Several aspects of lipoproteins and lipoprotein metabolism will be examined. Emphasis will be placed on the proatherogenic and thrombogenic effects of oxidized LDL.

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