Differential Effects of LOX-1 Inhibition on Aortic Structure and Posterior Cerebral Artery Structure and Function in an Experimental Model of Preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy marked by vascular dysfunction, large artery stiffness, and excess oxidized low-density lipoprotein (oxLDL). oxLDL activates oxidative stress pathways which contribute to arterial stiffness through interaction with the lectin-like oxLDL receptor 1 (LOX-1). Increased vascular stiffness is associated with higher pulse wave velocity and downstream microvasculature damage. Here we evaluated the ability of LOX-1 inhibition (LOX-1i) to prevent large artery structural and microvascular structural and functional changes via assessment of the descending thoracic aorta (DTAo) and posterior cerebral arteries (PCA) in a high cholesterol model of preeclampsia. Adult female Sprague Dawley normal late-pregnant (LP) and experimentally preeclamptic (ePE, high cholesterol diet d7-19) animals underwent intraperitoneal (i.p.) implantation of a mini-osmotic pump at d12 containing LOX-1 neutralizing antibodies (ePE + LOX-1i, n = 7) or goat IgG as vehicle control (LP + IgG, n = 8 and ePE + IgG, n = 8). Animals were studied at d19. DTAos and PCAs were removed for histologic assessment and isolated vessel experiments, respectively. Fetuses and placentas were weighed individually. Plasma was analyzed for markers of oxidative stress. ePE + IgG DTAo elastin content (an indirect metric of stiffness) was not significantly different from the LP + IgG group. Nonetheless, trending elastin break and sinuosity data (higher number of breaks and lower sinuosity in the ePE + IgG group compared to LP + IgG) suggested increased stiffness in this high cholesterol PE model. LOX-1i appeared to prevent a decrease in elastin. PCAs showed no structural changes with ePE or LOX-1i. ePE PCAs had increased reactivity to the nitric oxide donor sodium nitroprusside and decreased tone that was unaffected by LOX-1i. ePE animals had increased plasma oxLDL and 3-nitrotyrosine that was unaffected by LOX-1i. Taken together, LOX-1i may improve large artery stiffness without mitigation of the oxidative stress or cerebral microvascular dysfunction seen in ePE. Understanding these mechanisms is important in abating the long-term risks of preeclampsia.

Lutein, zeaxanthin, and meso-zeaxanthin supplementation attenuates inflammatory cytokines and markers of oxidative cardiovascular processes in humans.

BACKGROUND AND AIMS: Systemic inflammation and oxidation are primary contributors to the development of atherosclerosis. Oxidation of low-density lipoprotein (LDL) particles within the vascular endothelium has been hypothesized to be an initial step in the formation of atherosclerotic plaques, with inflammatory cytokines serving as the signaling mechanism for concomitant macrophage activation. Supplementation with the antioxidative macular xanthophylls (lutein [L], zeaxanthin [Z], and meso-zeaxanthin [MZ]) has been shown to aid in the reduction of inflammatory physiologic responses; therefore, we hypothesized that in our study population, supplementation with these xanthophylls would facilitate a systemic reduction in markers of inflammation and cardiovascular lipid oxidation. METHODS AND RESULTS: In this double-blind placebo-controlled supplementation study, participants were randomly allocated to receive the active intervention containing L (10 mg) + MZ (10 mg) + Z (2 mg) or placebo (containing sunflower oil). Serum concentrations of carotenoids (assessed by HPLC), inflammatory cytokines (IL-6, IL-1ß, TNF-α) and oxidized LDL (OxLDL; by solid-phase sandwich ELISA) were measured at baseline and at 6-months. Results showed that over the supplementation period, compared to placebo, the active group demonstrated statistically significant increases in serum concentrations of L, Z, & MZ (p < 0.05), reductions in inflammatory cytokines IL-1ß (p < 0.001) and TNF-α (p = 0.003), as well as a corresponding reduction in serum OxLDL (p = 0.009). CONCLUSIONS: Our data show that L, Z, & MZ supplementation results in decreased serum IL-1ß, TNF-α, and OxLDL. This suggests that these carotenoids are acting systemically to attenuate oxidative lipid products and inflammation, thus reducing their contribution to atherosclerotic plaque formation.

Macrophage-derived FGFR1 drives atherosclerosis through PLCγ-mediated activation of NF-κB inflammatory signaling pathway.

BACKGROUND: Atherosclerosis is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signaling in atherosclerosis are not known. In the present study, we investigated FGFR1 signaling in atherosclerosis development and progression. METHODS AND RESULTS: Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2. CONCLUSION: Our study provides evidence of a new FGFR1-PLCγ- NF-κB axis in macrophages in inflammatory atherosclerosis, supporting FGFR1 as a potentially therapeutic target for atherosclerosis-related diseases.

Comparative Analysis of Atherogenic Lipoproteins L5 and Lp(a) in Atherosclerotic Cardiovascular Disease.

PURPOSE OF REVIEW: Low-density lipoprotein (LDL) poses a risk for atherosclerotic cardiovascular disease (ASCVD). As LDL comprises various subtypes differing in charge, density, and size, understanding their specific impact on ASCVD is crucial. Two highly atherogenic LDL subtypes-electronegative LDL (L5) and Lp(a)-induce vascular cell apoptosis and atherosclerotic changes independent of plasma cholesterol levels, and their mechanisms warrant further investigation. Here, we have compared the roles of L5 and Lp(a) in the development of ASCVD. RECENT FINDINGS: Lp(a) tends to accumulate in artery walls, promoting plaque formation and potentially triggering atherosclerosis progression through prothrombotic or antifibrinolytic effects. High Lp(a) levels correlate with calcific aortic stenosis and atherothrombosis risk. L5 can induce endothelial cell apoptosis and increase vascular permeability, inflammation, and atherogenesis, playing a key role in initiating atherosclerosis. Elevated L5 levels in certain high-risk populations may serve as a distinctive predictor of ASCVD. L5 and Lp(a) are both atherogenic lipoproteins contributing to ASCVD through distinct mechanisms. Lp(a) has garnered attention, but equal consideration should be given to L5.

CXCL16-dependent scavenging of oxidized lipids by islet macrophages promotes differentiation of pathogenic CD8+ T cells in diabetic autoimmunity.

The pancreatic islet microenvironment is highly oxidative, rendering ß cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Texint) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16-/- mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals.

Profile of Lipoprotein Subclasses in Chinese Primary Open-Angle Glaucoma Patients.

To investigate the plasma lipoprotein subclasses in patients with primary open-angle glaucoma (POAG), a total of 20 Chinese POAG patients on intraocular pressure (IOP)-lowering treatment and 20 age-matched control subjects were recruited. Based on the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), the study subjects were divided into elevated- and normal-level subgroups. The plasma lipoprotein, lipoprotein subclasses, and oxidized LDL (oxLDL) levels were quantitatively measured. The discrimination potential of the lipoproteins was evaluated using the area under the receiver operating characteristic curve (AUC), and their correlation with clinical parameters was also evaluated. Compared to the control subjects with elevated TC and/or LDL-C levels, the levels of TC, LDL-C, non-high-density lipoprotein cholesterol (non-HDL), LDL subclass LDL3 and small dense LDL (sdLDL), and oxLDL were significantly higher in POAG patients with elevated TC and/or LDL-C levels. No differences in any lipoproteins or the subclasses were found between the POAG patients and control subjects with normal TC and LDL-C levels. Moderate-to-good performance of TC, LDL-C, non-HDL, LDL3, sdLDL, and oxLDL was found in discriminating between the POAG patients and control subjects with elevated TC and/or LDL-C levels (AUC: 0.710-0.950). Significant negative correlations between LDL3 and sdLDL with retinal nerve fiber layer (RNFL) thickness in the superior quadrant and between LDL3 and average RNFL thickness were observed in POAG patients with elevated TC and/or LDL-C levels. This study revealed a significant elevation of plasma lipoproteins, especially the LDL subclasses, in POAG patients with elevated TC and/or LDL-C levels, providing insights on monitoring specific lipoproteins in POAG patients with elevated TC and/or LDL-C.

We Must Abandon the Myth: Oxidized Low-density Lipoprotein is not a Lipoprotein that Plays a Key Role in Atherogenesis.

The purpose of this review is to revisit in detail the arguments supporting or disproving the hypothesis that oxidized low-density lipoprotein (LDL) plays a key role in atherosclerotic lesion development. The detection of oxidized LDL in vivo was extremely important for confirming its key role in atherogenesis. Indirect evidence of its existence included the presence of autoantibodies against malondialdehyde-treated LDL in human blood; however, the affinity of circulating antibodies to another LDL modification, such as desialylated LDL, was an order of magnitude stronger. At least 3 forms of atherogenic modified lipoproteins were isolated from the blood of atherosclerotic patients using different methods, namely, small dense, electronegative and desialylated. Their properties were so similar that it was suggested that the three types could be classified as the same multiple-modified LDL particle. It has been shown that when native (unmodified) LDL is incubated with autologous serum from patients with atherosclerosis, multiple modifications occur, which include desialylation, a decrease in the content of phospholipids and neutral lipids, a decrease in particle size, an increase in negative charge and other physical and chemical changes. Longer incubation also increased the susceptibility of LDL to oxidation. Thus, LDL oxidation is not the only, much less the most important, form of atherogenic modification of LDL since it occurs at the last stages of multiple modifications cascade and does not significantly increase the atherogenic potential of multiple-modified LDL. Finally, clinical trials did not support the oxidative hypothesis; however, research on oxidized LDL continues, influencing the future research. It is time to abandon the myth!

Uptake of ox-LDL by binding to LRP6 mediates oxidative stress-induced BMSCs senescence promoting obesity-related bone loss.

Obesity has long been thought to be a main cause of hyperlipidemia. As a systemic disease, the impact of obesity on organs, tissues and cells is almost entirely negative. However, the relationship between obesity and bone loss is highly controversial. On the one hand, obesity has long been thought to have a positive effect on bone due to increased mechanical loading on the skeleton, conducive to increasing bone mass to accommodate the extra weight. On the other hand, obesity-related metabolic oxidative modification of low-density lipoprotein (LDL) in vivo causes a gradual increase of oxidized LDL (ox-LDL) in the bone marrow microenvironment. We have reported that low-density lipoprotein receptor-related protein 6 (LRP6) acts as a receptor of ox-LDL and mediates the bone marrow stromal cells (BMSCs) uptake of ox-LDL. We detected elevated serum ox-LDL in obese mice. We found that ox-LDL uptake by LRP6 led to an increase of intracellular reactive oxygen species (ROS) in BMSCs, and N-acetyl-L-cysteine (NAC) alleviated the cellular senescence and impairment of osteogenesis induced by ox-LDL. Moreover, LRP6 is a co-receptor of Wnt signaling. We found that LRP6 preferentially binds to ox-LDL rather than dickkopf-related protein 1 (DKK1), both inhibiting Wnt signaling and promoting BMSCs senescence. Mesoderm development LRP chaperone (MESD) overexpression inhibits ox-LDL binding to LRP6, attenuating oxidative stress and BMSCs senescence, eventually rescuing bone phenotype.

Antibodies against oxidized LDL and atherosclerosis in rheumatoid arthritis patients treated with biological agents: a prospective controlled study.

OBJECTIVES: The aim of this study was to investigate the relation among atherosclerosis, antibodies against oxidized LDL (anti-oxLDL), and inflammation in rheumatoid arthritis (RA) patients treated with biological (b) disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Fifty-nine patients who were receiving conventional synthetic DMARDs and were eligible for treatment with a biological agent were included in the study. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and IgG antibodies against oxidized LDL (anti-oxLDL) as well as carotid intima-media thickness (cIMT) were determined before and after 6 months of treatment. Thirty-one healthy individuals were used as a control group. RESULTS: At baseline, RA patients had lower TC and HDL-C levels and increased cIMT compared to controls. After a 6-month follow-up, the re-evaluation of carotids revealed a statistically important decrease of cIMT values. This observation was accompanied by a statistically important elevation of HDL-C levels and a reduction of the titer of anti-oxLDL antibodies regardless of the bDMARD that was administered. No statistically significant association was found between the cIMT and anti-oxLDL, HDL-C, CRP, or DAS28 score neither before nor 6 months after treatment using linear regression analyses adjusted for age and gender. CONCLUSIONS: We provide evidence that atherogenic lipid profile and ongoing atherosclerosis which characterize RA patients appear to improve after biological therapy, and we also suggest a possible atherogenic effect of IgG anti-ox LDL antibodies.

The lack of association between different LDL-C levels and oxidized LDL in patients with type 2 diabetes.

Background: High concentrations of low-density lipoprotein cholesterol (LDL-C) have been a known risk factor for cardiovascular diseases. Also, the role of oxidized LDL (ox-LDL) in forming atherosclerosis plaque has been proven. However, it has not yet been proven that atherogenic LDL-C by-products like ox-LDL will decrease by keeping the LDL levels at the desired level. This study aimed to examine the relationship between LDL-C and ox-LDL in different LDL-C values in patients with type 2 diabetes (T2D). Methods: In this cross-sectional study, 347 patients with T2D who received statins were enrolled. LDL-C values were defined into four groups as LDL-C < 55 mg/dL, 55 mg/dL ≤ to <70 mg/dL, 70 mg/dL ≤ to <100 mg/dL and LDL-C ≥ 100 mg/dL. Total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and ox-LDL were studied in the four defined groups. Results: Ox-LDL levels were not different among the four groups (p = 0.30). In addition, LDL-C and ox-LDL levels had no significant correlation (r = 0.480, p = 0.376). Additionally, based on this study analysis, ox-LDL levels were significantly correlated with TG levels (r = 0.119, p < 0.05) and TG/HDL ratio (r = 0.390, p < 0.01). Conclusions: It is concluded that ox-LDL levels were not associated with different LDL-C level categories from <55 mg/dL to >100 mg/dL in patients with T2D. However, the revealed association of ox-LDL with TG level and TG/HDL ratio may be considered in the clinic.

Relationship of Soluble Lectin-Like Low-Density Lipoprotein Receptor-1 (sLOX-1) With Inflammation and Coronary Plaque Progression in Psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory condition associated with coronary artery disease risk. Uptake of oxidized low-density lipoprotein by the lectin-like low-density lipoprotein receptor-1 triggers release of the soluble extracellular domain of the receptor (sLOX-1). We sought to characterize the relationship between sLOX-1, inflammation, and coronary plaque progression in psoriasis. METHODS AND RESULTS: A total of 327 patients with psoriasis had serum sLOX-1 levels measured at baseline by an ELISA-based assay. Stratification by high-sensitivity C-reactive protein ≥4.0 mg/L (quartile 4), identified 81 participants who had coronary plaque phenotyping at baseline and were followed longitudinally by coronary computed tomography angiography. Subjects within high-sensitivity C-reactive protein quartile 4 were middle-aged (51.47±12.62 years), predominantly men (54.3%) with moderate psoriasis disease severity (6.60 [interquartile range, 3.30-13.40]). In the study cohort, participants with sLOX-1 above the median displayed increased vulnerable coronary plaque features. At baseline, sLOX-1 was associated with total burden (rho=0.296; P=0.01), noncalcified burden (rho=0.286; P=0.02), fibro-fatty burden (rho=0.346; P=0.004), and necrotic burden (rho=0.394; P=0.002). A strong relationship between sLOX-1, noncalcified burden (ß=0.19; P=0.03), and fibro-fatty burden (ß=0.29; P=0.003) was found in fully adjusted models at baseline and 1- and 4-year follow-up. Finally, coronary plaque features progressed over 1 year regardless of biologic or systemic treatment in subjects with high sLOX-1. CONCLUSIONS: Patients with psoriasis with both high sLOX-1 and high-sensitivity C-reactive protein levels have increased coronary plaque burden associated with atherosclerotic plaque progression independent of biologic and systemic treatment. Thus, sLOX-1 might be considered as a promising marker in coronary artery disease risk estimation beyond traditional risk factors. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01778569.

Effectiveness of Regular Aerobic Exercise in Improving Vascular Stiffness in Elderly Korean Women.

The purpose of this study was to determine the effects of aerobic exercise on carotid to femoral pulse wave velocity (cf-PWV), cell adhesion molecules (intracellular adhesion molecules (ICAM-1), vascular cell adhesion molecules (VCAM-1), endothelial selectin (E-selectin), and oxidized LDL in elderly women aged 70-85 years, and to identify the effect of and correlation with vascular stiffness. Forty participants were recruited and divided into three groups; vascular stiffness (VSG, n = 14), obesity (OG, n = 14), and normal (NG, n = 12). All groups were given a 16-week intervention of aerobic exercise, and the data collected before and after exercise were analyzed using SPSS Ver. 23.0. Two-way repeated-measures ANOVA was used to evaluate between-group and time-dependent interaction effects. One-way ANOVA was used to evaluate between-group variations. In addition, the significance was tested using a post hoc test (Scheffe). The within-group variations by time before and after exercise were examined using a paired t-test, and correlation analysis was performed using Pearson correlation coefficients. Simple regression analysis was performed for variables showing significant differences. The results indicate interaction effects for cf-PWV (p < 0.001), VCAM-1 (p < 0.01), E-selectin (p < 0.05), and oxidized LDL (p < 0.001). The rate of change of cf-PWV was positively correlated with that of VCAM-1 (r = 0.352, p < 0.05) and that of oxidized LDL (r = 0.325, p < 0.05) with statistical significance. To determine the effect of the rate of change of cf-PWV on the rate of change of VCAM-1, the variables were tested, and the coefficient of determination in the regression analysis was 0.124, indicating that 12.4% of the tested variables fit the standard regression line. The variables for the effect of the rate of change of cf-PWV on the rate of change of oxidized LDL were also tested, and the coefficient of determination in the regression analysis was 0.106, indicating that 10.6% of the tested variables fit the standard regression line. Thus, the 16-week regular and consistent aerobic exercise program had significant effects on the cf-PWV, ICAM-1, VCAM-1, E-selectin, and oxidized LDL in elderly Korean women with vascular stiffness, suggesting improvements in vascular stiffness, based on which the intervention is predicted to contribute to the prevention of vascular dysfunction by lowering the risk of cardiovascular disease due to atherosclerosis, as well as having a positive effect in the prevention of impairment of vascular endothelial cells.

The Impacts of Animal-Based Diets in Cardiovascular Disease Development: A Cellular and Physiological Overview.

Cardiovascular disease (CVD) is the leading cause of death in the United States, and diet plays an instrumental role in CVD development. Plant-based diets have been strongly tied to a reduction in CVD incidence. In contrast, animal food consumption may increase CVD risk. While increased serum low-density lipoprotein (LDL) cholesterol concentrations are an established risk factor which may partially explain the positive association with animal foods and CVD, numerous other biochemical factors are also at play. Thus, the aim of this review is to summarize the major cellular and molecular effects of animal food consumption in relation to CVD development. Animal-food-centered diets may (1) increase cardiovascular toll-like receptor (TLR) signaling, due to increased serum endotoxins and oxidized LDL cholesterol, (2) increase cardiovascular lipotoxicity, (3) increase renin-angiotensin system components and subsequent angiotensin II type-1 receptor (AT1R) signaling and (4) increase serum trimethylamine-N-oxide concentrations. These nutritionally mediated factors independently increase cardiovascular oxidative stress and inflammation and are all independently tied to CVD development. Public policy efforts should continue to advocate for the consumption of a mostly plant-based diet, with the minimization of animal-based foods.

Free Radicals and Obesity-Related Chronic Inflammation Contrasted by Antioxidants: A New Perspective in Coronary Artery Disease.

We are surrounded by factors called free radicals (FR), which attach to the molecules our body is made of, first among them the endothelium. Even though FR are to a certain extent a normal factor, nowadays we face an escalating increase in these biologically aggressive molecules. The escalating formation of FR is linked to the increased usage of man-made chemicals for personal care (toothpaste, shampoo, bubble bath, etc.), domestic laundry and dish-washer detergents, and also an ever wider usage of drugs (both prescription and over the counter), especially if they are to be used long-term (years). In addition, tobacco smoking, processed foods, pesticides, various chronic infectious microbes, nutritional deficiencies, lack of sun exposure, and, finally, with a markedly increasing impact, electromagnetic pollution (a terribly destructive factor), can increase the risk of cancer, as well as endothelial dysfunction, owing to the increased production of FR that they cause. All these factors create endothelial damage, but the organism may be able to repair such damage thanks to the intervention of the immune system supported by antioxidants. However, one other factor can perpetuate the state of inflammation, namely obesity and metabolic syndrome with associated hyperinsulinemia. In this review, the role of FR, with a special emphasis on their origin, and of antioxidants, is explored from the perspective of their role in causing atherosclerosis, in particular at the coronary level.

Novel oxidized LDL-based clinical markers in peritoneal dialysis patients for atherosclerosis risk assessment.

Maintenance peritoneal dialysis (PD) is commonly associated with cardiovascular diseases (CVDs), whose risk is assessed via LDL-C. Nonetheless, oxidized LDL (oxLDL), as being a key component of atherosclerotic lesions, could be also associated with atherosclerosis and related CVDs. However, its predictive value for CVDs risk assessment is subject of research studies due to the lack of specific methods to measure oxLDL status from its individual lipid/protein components. In the present study, six novel oxLDL markers, representative of certain oxidative modifications on the LDL protein and lipid components, are measured in atherosclerosis-prone PD patients (39) versus those in chronic kidney disease patients (61) under hemodialysis (HD) and healthy controls (40). LDL from serum of PD, HD and control subjects were isolated and fractionated into cholesteryl esters, triglycerides, free cholesterol, phospholipids and apolipoprotein B100 (apoB100). Subsequently the oxLDL markers cholesteryl ester hydroperoxides (-OOH), triglyceride-OOH, free cholesterol-OOH, phospholipid-OOH, apoB100 malondialdehyde and apoB100 dityrosines were measured. LDL carotenoid levels and LDL particle serum concentration were also measured. The levels of all oxLDL lipid-OOH markers were significantly elevated in PD patients versus control, while the levels of cholesteryl ester-/triglyceride-/free cholesterol-OOH were significantly elevated in PD versus HD patients, regardless of patients' underlying medical conditions, sex, age, PD type, clinical biochemical markers and medication. It should be noted that all fractionated lipid-OOH levels were inversely correlated with LDL-P concentration, while LDL-P concentration was not correlated with LDL-C in PD patients. Moreover, LDL carotenoids were significantly lower in PD patients versus control. The increased levels of oxLDL status specific markers in both PD and HD patients (compared to control), support a potential prognostic value of oxLDL regarding CVD risk assessment in both patient groups. Lastly, the study introduces the oxLDL peroxidation markers free cholesterol-OOH and cholesteryl ester-OOH as complementary to LDL-P number, and as possible alternatives to LDL-C.

Oxidized low-density lipoprotein regulates macrophage polarization in atherosclerosis.

Atherosclerosis is the pathological basis of acute cardiovascular and cerebrovascular diseases. Oxidized LDL has been recognized as a major atherogenic factor in the vessel wall for decades. A growing body of evidence suggests that oxidized LDL modulates macrophage phenotypes in atherosclerosis. This article reviews the research progress on the regulation of macrophage polarization by oxidized LDL. Mechanistically, oxidized LDL induces macrophage polarization via cell signaling, metabolic reprogramming, epigenetic regulation, and intercellular regulation. This review is expected to provide new targets for the treatment of atherosclerosis.

Oxidized LDL-mediated upregulation of ADAMTS-4 in monocytes/macrophages involves ROS-NF-κB-SIRT-1 pathway.

Background and aims: ADAMTS-4 is a protease enzyme involved in vascular remodeling and atherosclerosis. It was found to be upregulated in macrophages seen in atherosclerotic lesions. This study aimed to investigate the expression and regulation of ADAMTS-4 in oxidized LDL-induced human monocytes/macrophages system. Methods: Peripheral blood mononuclear cells (PBMCs) isolated from human blood, and treated with oxidized LDL (50 µg mL-1) were used as the model system for the study. mRNA and protein expressions were studied by PCR, ELISA, and western blot analysis. ROS production and cell viability were determined by DCFDA staining and MTT assay, respectively. Results: In the presence of oxidized LDL, monocytes get differentiated into macrophages, which were confirmed by the increased expression of macrophage differentiation markers and pro-inflammatory cytokine TNF-α. Oxidized LDL increased the mRNA and protein expression of ADAMTS-4 in monocytes/macrophages. N- Acetyl cysteine, ROS scavenger, downregulate the protein expression of ADAMTS-4. The expression of ADAMTS-4 was decreased significantly in the presence of NF-κB inhibitors. SIRT-1 activity was significantly downregulated in the macrophages and was reversed in the presence of the SIRT-1 agonist, resveratrol. Acetylation of NF-κB and hence the expression of ADAMTS-4 were significantly downregulated in the presence of SIRT-1 activator, resveratrol. Conclusions: Our study suggests that oxidized LDL significantly upregulated the expression of ADAMTS-4 in the monocytes/macrophages through ROS- NF-κB- SIRT-1 pathway.

Increase in gut permeability and oxidized ldl is associated with post-acute sequelae of SARS-CoV-2.

Background: Post-acute sequelae of SARS-CoV-2 (PASC) is marked by persistent or newly developing symptoms beyond 4 weeks of infection. Investigating gut integrity, oxidized lipids and inflammatory markers is important for understanding PASC pathogenesis. Methods: A cross-sectional study including COVID+ with PASC, COVID+ without PASC, and COVID-negative (COVID-) participants. We measured plasma markers by enzyme-linked immunosorbent assay to assess intestinal permeability (ZONULIN), microbial translocation (lipopolysaccharide-binding protein or LBP), systemic inflammation (high-sensitivity C-reactive protein or hs-CRP), and oxidized low-density lipoprotein (Ox-LDL). Results: 415 participants were enrolled in this study; 37.83% (n=157) had prior COVID diagnosis and among COVID+, 54% (n=85) had PASC. The median zonulin among COVID- was 3.37 (IQR: 2.13, 4.91) mg/mL, 3.43 (IQR: 1.65, 5.25) mg/mL among COVID+ no PASC, and highest [4.76 (IQR: 3.2, 7.35) mg/mL] among COVID+ PASC+ (p<.0001). The median ox-LDL among COVID- was 47.02 (IQR: 35.52, 62.77) U/L, 57.24 (IQR: 40.7, 75.37) U/L among COVID+ No PASC, and the highest [76.75 (IQR: 59.95, 103.28) U/L] among COVID+ PASC+ (p<.0001). COVID+ PASC+ was positively associated with zonulin (p=0.0002) and ox-LDL (p<.0001), and COVID- was negatively associated with ox-LDL (p=0.01), compared to COVID+ No PASC. Every unit increase in zonulin was associated with 44% higher predicted odds of having PASC [aOR: 1.44 (95%CI: 1.1, 1.9)] and every one-unit increase in ox-LDL was associated with more than four-fold increased odds of having PASC [aOR: 2.44 (95%CI: 1.67, 3.55)]. Conclusions: PASC is associated with increased gut permeability and oxidized lipids. Further studies are needed to clarify whether these relationships are causal which could lead to targeted therapeutics.