-
Autoimmunity Dec 2023Nuclear receptor subfamily 3 group C member 2 (NR3C2) has been revealed to affect the progression of multiple inflammatory diseases, while NR3C2's efficacy in coronary...
Nuclear receptor subfamily 3 group C member 2 (NR3C2) has been revealed to affect the progression of multiple inflammatory diseases, while NR3C2's efficacy in coronary artery disease (CAD) remains largely unsolved. The study intended to elucidate the possible mechanisms of NR3C2 in oxidised low density lipoprotein (ox-LDL)-induced inflammation in human coronary endothelial cells (HCAECs) regulating NACHT, LRR, and PYD domains-containing protein 3 (NLRP3). Patients who underwent CT angiography or coronary angiography for suspected CAD in our hospital were collected. The patients were divided into the CAD and the non-CAD (NCAD) groups. The expression of NR3C2 and NLRP3 in the peripheral blood of patients in both groups was examined by RT-qPCR. HCAECs were treated with ox-LDL to establish the model. The expression of NR3C2 and NLRP3 in ox-LDL-induced HCAECs was tested by RT-qPCR. The proliferation of HCAECs was measured using CCK-8 assay, the apoptosis of HCAECs was assessed by flow cytometry, and the levels of inflammation-related factors IL-1β and IL-18 in the cell supernatant were evaluated by ELISA. The molecular mechanisms of these factors in the proliferation and apoptosis of HCAECs and in the inflammatory response were further determined by knockdown and overexpression systems. The relationship between NR3C2 and NLRP3 was determined by ChIP and luciferase activity assays and bioinformatics analysis. NR3C2 and NLRP3 levels were elevated in the serum of CAD patients. The ox-LDL treatment elevated NR3C2 levels, evoked apoptosis and inflammation, and impeded cell viability in HCAECs, whereas downregulation of NR3C2 increased cell viability and reduced apoptosis and inflammatory response in ox-LDL-induced inflammation in HCAECs. NR3C2 levels were positively correlated with NLRP3, and NR3C2 elevated NLRP3 expression through transcription. Overexpression of NLRP3 counteracted the impacts of silencing NR3C2 on cell viability, cell apoptosis, and inflammatory response in ox-LDL-induced HCAECs. Our research stresses that NR3C2 transcription promotes NLRP3 to induce inflammatory responses in ox-LDL-induced HCAECs.
Topics: Humans; Apoptosis; Endothelial Cells; Inflammasomes; Lipoproteins, LDL; MicroRNAs; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, Mineralocorticoid
PubMed: 36919662
DOI: 10.1080/08916934.2023.2189135 -
Brazilian Journal of Medical and... 2021Dendritic cells (DCs) play a crucial role as central orchestrators of immune system response in atherosclerosis initiation and progression. Lectin-like oxidized...
Dendritic cells (DCs) play a crucial role as central orchestrators of immune system response in atherosclerosis initiation and progression. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in the immune maturation of DCs, but the underlying mechanisms remain unclear. We isolated mouse bone marrow progenitors and stimulated them with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4 to induce immature DCs. We then treated DCs with oxidized low-density lipoprotein (oxLDL) to induce maturation. LOX-1 siRNA was used to investigate the modulation of LOX-1 on the development of DCs and the underlying signal pathways. CD11c-positive DCs were successfully derived from mouse bone marrow progenitors. OxLDL promoted the expressions of DCs maturation markers and pro-inflammatory cytokines. OxLDL also upregulated LOX-1 expression and activated MAPK/NF-κB pathways. LOX-1 siRNA could attenuate the expression of MAPK/NF-κB pathways and inflammatory cytokines. In conclusion, oxLDL induced the maturation of DCs via LOX-1-mediated MAPK/NF-κB pathway, which contributed to the initiation and progression of atherosclerosis.
Topics: Animals; Dendritic Cells; Lipoproteins, LDL; MAP Kinase Signaling System; Mice; NF-kappa B; Scavenger Receptors, Class E
PubMed: 34076144
DOI: 10.1590/1414-431X2021e11062 -
Pediatric Nephrology (Berlin, Germany) Oct 2019Low-density lipoprotein (LDL) apheresis has been used increasingly in clinical practice for the treatment of renal diseases with nephrotic syndrome (NS), specifically... (Review)
Review
Low-density lipoprotein (LDL) apheresis has been used increasingly in clinical practice for the treatment of renal diseases with nephrotic syndrome (NS), specifically focal segmental glomerulosclerosis (FSGS). Persistent hyperlipidemia for prolonged periods is nephrotoxic and leads to chronic progressive glomerular and tubulointerstitial injury. Effective management of hyperlipidemia with HMG-CoA reductase inhibitors or LDL apheresis in drug-resistant NS patients may prevent the progression of renal disease and, in some patients, resolution of NS symptoms. Available literature reveals beneficial effects of LDL apheresis for NS refractory to drug therapy. Here we update on the current understanding of lipid nephrotoxicity and application of LDL apheresis to prevent progression of renal diseases.
Topics: Animals; Blood Component Removal; Child; Disease Models, Animal; Disease Progression; Glomerulosclerosis, Focal Segmental; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Kidney Glomerulus; Lipid Metabolism; Lipoproteins, LDL; Nephrotic Syndrome; Renal Elimination; Treatment Outcome
PubMed: 30218191
DOI: 10.1007/s00467-018-4061-9 -
Journal of Internal Medicine Jul 2024Platelet hyperreactivity and hyperlipidaemia contribute significantly to atherosclerosis. Thus, it is desirable to review the platelet-hyperlipidaemia interplay and its... (Review)
Review
Platelet hyperreactivity and hyperlipidaemia contribute significantly to atherosclerosis. Thus, it is desirable to review the platelet-hyperlipidaemia interplay and its impact on atherogenesis. Native low-density lipoprotein (nLDL) and oxidized LDL (oxLDL) are the key proatherosclerotic components of hyperlipidaemia. nLDL binds to the platelet-specific LDL receptor (LDLR) ApoE-R2', whereas oxLDL binds to the platelet-expressed scavenger receptor CD36, lectin-type oxidized LDLR 1 and scavenger receptor class A 1. Ligation of nLDL/oxLDL induces mild platelet activation and may prime platelets for other platelet agonists. Platelets, in turn, can modulate lipoprotein metabolisms. Platelets contribute to LDL oxidation by enhancing the production of reactive oxygen species and LDLR degradation via proprotein convertase subtilisin/kexin type 9 release. Platelet-released platelet factor 4 and transforming growth factor β modulate LDL uptake and foam cell formation. Thus, platelet dysfunction and hyperlipidaemia work in concert to aggravate atherogenesis. Hypolipidemic drugs modulate platelet function, whereas antiplatelet drugs influence lipid metabolism. The research prospects of the platelet-hyperlipidaemia interplay in atherosclerosis are also discussed.
Topics: Humans; Atherosclerosis; Hyperlipidemias; Blood Platelets; Lipoproteins, LDL; Platelet Activation; Receptors, LDL; Hypolipidemic Agents
PubMed: 38704820
DOI: 10.1111/joim.13794 -
Journal of Oral Biosciences Mar 2023Epidemiologically, correlations between periodontal disease activity and CVD/serum lipid-related condition have been reported. Known mediators of these links include... (Review)
Review
BACKGROUND
Epidemiologically, correlations between periodontal disease activity and CVD/serum lipid-related condition have been reported. Known mediators of these links include triglycerides, oxidized LDL (oxLDL) and inflammatory cytokines such as TNF-α supplied by adipocytes as well as oxidative degeneration products of these lipids. In this review, we focused on oxidized LDL and considered the relationship between periodontal disease and systemic conditions.
HIGHLIGHT
The degree of oxidation in the periodontal pocket can be evaluated by analyzing the Gingival Cervicular Fluid (GCF), which can be easily collected with paperpoint. The oxLDL/LDL ratio in GCF has been shown to be 17 times as high as that in blood, and IL-8 and IL-1β were also abundantly found in GCF. Periodontal treatment significantly lowers oxLDL levels in not only GCF but also plasma. In addition, there has been growing body of evidence that periodontal infections by periodontopathic bacteria affect arteriosclerosis. On the other hands, neutrophil extracellular traps (NETs), a form of innate immune responses, reportedly play a role as a defense mechanism in the periodontal pockets. However, the regulatory mechanism of NETs in periodontal pocket is still unknown. Recently, NETs induced by oxidized cholesterol have been reported to be involved in inflammatory damage to vascular endothelial cells.
CONCLUSION
Further understanding of the newly discovered roles of oxLDL in the defense and destruction of periodontal tissues are anticipated.
Topics: Humans; Periodontal Pocket; Endothelial Cells; Periodontitis; Lipoproteins, LDL; Periodontal Diseases
PubMed: 36206991
DOI: 10.1016/j.job.2022.09.006 -
International Journal of Molecular... Apr 2023Cardiovascular disease (CVD) impacts hundreds of millions of people each year and is the main cause of death worldwide, with atherosclerosis being its most frequent form... (Review)
Review
Cardiovascular disease (CVD) impacts hundreds of millions of people each year and is the main cause of death worldwide, with atherosclerosis being its most frequent form of manifestation. Low-density lipoproteins (LDL) have already been established as a significant cardiovascular risk factor, but more recent studies have shown that small, dense LDLs are the ones more frequently associated with a higher overall risk for developing atherosclerotic cardiovascular disease. Ever since atherogenic phenotypes were defined for the first time, LDL subfractions have been continuously analyzed in order to identify those with a higher atherogenic profile that could further become not only high-accuracy, effective prognostic biomarkers, but also treatment targets for novel lipid-lowering molecules. This review sets out to comprehensively evaluate the association between various LDL-subfractions and the risk of further developing major adverse cardiovascular events, by assessing both genetical and clinical features and focusing on their physiopathological characteristics, chemical composition, and global ability to predict long-term cardiovascular risk within the general population. Further research is required in order to establish the most beneficial range of LDL-C levels for both primary and secondary prevention, as well as to implement LDL subfraction testing as a routine protocol, separately from the general assessment of the other traditional cardiovascular risk factors.
Topics: Humans; Cardiovascular Diseases; Lipoproteins, LDL; Atherosclerosis
PubMed: 37047642
DOI: 10.3390/ijms24076669 -
The American Journal of Cardiology Mar 2024
Topics: Humans; Cardiovascular Diseases; Atherosclerosis; Lipoproteins, LDL; Cholesterol
PubMed: 38272202
DOI: 10.1016/j.amjcard.2024.01.016 -
The Protein Journal Apr 2021Cytosolic estrogen sulfotransferase (SULT1E) mainly catalyzes the sulfate conjugation of estrogens, which decrease atherosclerosis progression. Recently we reported that...
Cytosolic estrogen sulfotransferase (SULT1E) mainly catalyzes the sulfate conjugation of estrogens, which decrease atherosclerosis progression. Recently we reported that a YKEG sequence in human SULT1E1 (hSULT1E1) corresponding to residues 61-64 can bind specifically to oxidized low-density lipoprotein (Ox-LDL), which plays a major role in the pathogenesis of atherosclerosis; its major oxidative lipid component lysophosphatidylcholine (LPC), and its structurally similar lipid, platelet-activating factor (PAF). In this study, we investigated the effect of Ox-LDL on the sulfating activity of hSULT1E1. In vivo experiments using a mouse model of atherosclerosis showed that the protein expression of SULT1E1 was higher in the aorta of mice with atherosclerosis compared with that in control animals. Results from a sulfating activity assay of hSULT1E1 using 1-hydroxypyrene as the substrate demonstrated that Ox-LDL, LPC, and PAF markedly decreased the sulfating activity of hSULT1E1, whereas native LDL and 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) as one of the oxidized phosphatidylcholines showed the opposite effect. The sulfating activity greatly changed in the presence of LPC, PAF, and POVPC in their concentration-dependen manner (especially above their critical micelle concentrations). Moreover, Ox-LDL specifically recognized dimeric hSULT1E1. These results suggest that the effects of Ox-LDL and native LDL on the sulfating activity of hSULT1E1 might be helpful in elucidating the novel mechanism underlying the pathogenesis of atherosclerosis, involving the relationship between estrogen metabolism, LDL, and Ox-LDL.
Topics: Animals; Atherosclerosis; Humans; Lipoproteins, LDL; Lysophosphatidylcholines; Male; Mice; Mice, Knockout; Platelet Activating Factor; Protein Binding; Sulfotransferases
PubMed: 33665770
DOI: 10.1007/s10930-021-09971-y -
Molecular Genetics and Metabolism Apr 2023Low-density lipoprotein (LDL) plasma concentration decline is a biomarker for acute inflammatory diseases, including coronavirus disease-2019 (COVID-19). Phenotypic...
BACKGROUND AND AIMS
Low-density lipoprotein (LDL) plasma concentration decline is a biomarker for acute inflammatory diseases, including coronavirus disease-2019 (COVID-19). Phenotypic changes in LDL during COVID-19 may be equally related to adverse clinical outcomes.
METHODS
Individuals hospitalized due to COVID-19 (n = 40) were enrolled. Blood samples were collected on days 0, 2, 4, 6, and 30 (D0, D2, D4, D6, and D30). Oxidized LDL (ox-LDL), and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were measured. In a consecutive series of cases (n = 13), LDL was isolated by gradient ultracentrifugation from D0 and D6 and was quantified by lipidomic analysis. Association between clinical outcomes and LDL phenotypic changes was investigated.
RESULTS
In the first 30 days, 42.5% of participants died due to Covid-19. The serum ox-LDL increased from D0 to D6 (p < 0.005) and decreased at D30. Moreover, individuals who had an ox-LDL increase from D0 to D6 to over the 90th percentile died. The plasma Lp-PLA2 activity also increased progressively from D0 to D30 (p < 0.005), and the change from D0 to D6 in Lp-PLA2 and ox-LDL were positively correlated (r = 0.65, p < 0.0001). An exploratory untargeted lipidomic analysis uncovered 308 individual lipids in isolated LDL particles. Paired-test analysis from D0 and D6 revealed higher concentrations of 32 lipid species during disease progression, mainly represented by lysophosphatidyl choline and phosphatidylinositol. In addition, 69 lipid species were exclusively modulated in the LDL particles from non-survivors as compared to survivors.
CONCLUSIONS
Phenotypic changes in LDL particles are associated with disease progression and adverse clinical outcomes in COVID-19 patients and could serve as a potential prognostic biomarker.
Topics: Humans; 1-Alkyl-2-acetylglycerophosphocholine Esterase; COVID-19; Lipoproteins, LDL; Biomarkers; Lysophosphatidylcholines
PubMed: 36889041
DOI: 10.1016/j.ymgme.2023.107552 -
The Journal of International Medical... Jun 2020Osteoarthritis (OA) is a chronic joint disorder that causes degeneration of cartilage, synovial inflammation, and formation of osteophytes. Aging, obesity, and sex are... (Review)
Review
Osteoarthritis (OA) is a chronic joint disorder that causes degeneration of cartilage, synovial inflammation, and formation of osteophytes. Aging, obesity, and sex are considered the main risk factors of OA. Recent studies have suggested that metabolic syndrome (MetS) disorders, such as hypertension, hyperlipidemia, diabetes mellitus, and obesity, may be involved in the pathogenesis and progression of OA. MetS disorders are common diseases that also result in atherosclerosis. Researchers believe that OA and atherosclerosis have underlying similar molecular mechanisms because the prevalence of both diseases increases with age. Oxidation of low-density lipoprotein (ox-LDL) is believed to play a role in the pathogenesis of atherosclerosis. Recent reports have shown that ox-LDL and low-density lipoprotein receptor 1 (LOX-1) are involved in the pathogenesis of OA. The purpose of this narrative review is to summarize the current understanding of the role of the LOX-1/ox-LDL system in the pathogenesis of OA and to reveal common underlying molecular pathways that are shared by MetS in OA and the LOX-1/ox-LDL system.
Topics: Atherosclerosis; Cartilage, Articular; Chondrocytes; Humans; Knee Joint; Lipoproteins, LDL; Osteoarthritis; Oxidation-Reduction
PubMed: 32552129
DOI: 10.1177/0300060520931609