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Journal of Extracellular Vesicles Nov 2023Extracellular vesicles (EVs) in blood plasma are recognized as potential biomarkers for disease. Although blood plasma is easily obtainable, analysis of EVs at the...
Extracellular vesicles (EVs) in blood plasma are recognized as potential biomarkers for disease. Although blood plasma is easily obtainable, analysis of EVs at the single particle level is still challenging due to the biological complexity of this body fluid. Besides EVs, plasma contains different types of lipoproteins particles (LPPs), that outnumber EVs by orders of magnitude and which partially overlap in biophysical properties such as size, density and molecular makeup. Consequently, during EV isolation LPPs are often co-isolated. Furthermore, physical EV-LPP complexes have been observed in purified EV preparations. Since co-isolation or association of LPPs can impact EV-based analysis and biomarker profiling, we investigated the presence and formation of EV-LPP complexes in biological samples by using label-free atomic force microscopy, cryo-electron tomography and synchronous Rayleigh and Raman scattering analysis of optically trapped particles and fluorescence-based high sensitivity single particle flow cytometry. Furthermore, we evaluated the impact on flow cytometric analysis in the presence of LPPs using in vitro spike-in experiments of purified tumour cell line-derived EVs in different classes of purified human LPPs. Based on orthogonal single-particle analysis techniques we demonstrate that EV-LPP complexes can form under physiological conditions. Furthermore, we show that in fluorescence-based flow cytometric EV analysis staining of LPPs, as well as EV-LPP associations, can influence quantitative and qualitative EV analysis. Lastly, we demonstrate that the colloidal matrix of the biofluid in which EVs reside impacts their buoyant density, size and/or refractive index (RI), which may have consequences for down-stream EV analysis and EV biomarker profiling.
Topics: Humans; Extracellular Vesicles; Single Molecule Imaging; Biomarkers; Cell Line, Tumor; Lipoproteins, LDL
PubMed: 37942918
DOI: 10.1002/jev2.12376 -
Hellenic Journal of Cardiology : HJC =... 2023Cross-sectional studies have shown that remnant cholesterol (RC) was associated with arterial stiffness. The present study evaluated the association of RC and the...
BACKGROUND
Cross-sectional studies have shown that remnant cholesterol (RC) was associated with arterial stiffness. The present study evaluated the association of RC and the discordance between RC and low-density lipoprotein cholesterol (LDL-C) with arterial stiffness progression.
METHODS
Data were derived from the Kailuan study. RC was calculated as total cholesterol - high-density lipoprotein cholesterol - LDL-C. Discordant RC with LDL-C were defined by residuals, cutoff points, and median values. Arterial stiffness progression was assessed by the brachial-ankle pulse wave velocity (baPWV) change, baPWV change rate, and increase/persistently high baPWV. Multivariable linear regression models and logistic regression models were used to explore the association of RC and discordant RC versus LDL-C with the arterial stiffness progression.
RESULTS
A total of 10,507 participants were enrolled in this study, with the mean age of 50.8 ± 11.8 years, 60.9% (6,396) of male. Multivariable regression analyses showed that, each 1 mmol/L increase in the RC level was associated with a 12.80 cm/s increase in baPWV change, a 3.08 cm/s/year increase in the baPWV change rate, and 13% (95% CI, 1.05-1.21) of increase in the risk for increase in/persistently high baPWV. Discordant high RC was associated with a 13.65 cm/s increase in baPWV change and 19% (95% CI, 1.06-1.33) of increase in the risk for increase in/persistently high baPWV compared to those with concordant group.
CONCLUSION
Discordantly high RC with LDL-C was associated with an increased risk of arterial stiffness progression. The findings demonstrated that RC may be an important marker of future coronary artery disease risk.
Topics: Humans; Male; Adult; Middle Aged; Cholesterol, LDL; Ankle Brachial Index; Vascular Stiffness; Cross-Sectional Studies; Pulse Wave Analysis; Cholesterol
PubMed: 37245643
DOI: 10.1016/j.hjc.2023.05.008 -
Cellular and Molecular Gastroenterology... 2024Observational studies have linked lipid-lowering drug targets pro-protein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) with adverse liver...
BACKGROUND & AIMS
Observational studies have linked lipid-lowering drug targets pro-protein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) with adverse liver outcomes; however, liver disease incidence varies across diverse populations, and the long-term hepatic impact of these lipid-lowering drugs among non-white Europeans remains largely unknown.
METHODS
We use single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR loci from genome-wide association study data of low-density lipoprotein cholesterol in 4 populations (East Asian [EAS], South Asian [SAS], African [AFR], and European [EUR]) to perform drug-target Mendelian randomization investigating relationships between PCSK9 and HMGCR inhibition and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin.
RESULTS
Analyses of PCSK9 instruments, including functional variants R46L and E670G, failed to find evidence for relationships of low-density lipoprotein cholesterol lowering via PCSK9 variants and adverse effects on ALT, AST, GGT, or ALP among the cohorts. PCSK9 inhibition was associated with increased direct bilirubin levels in EUR (β = 0.089; P value = 5.69 × 10) and, nominally, in AFR (β = 0.181; P value = .044). HMGCR inhibition was associated with reduced AST in SAS (β = -0.705; P value = .005) and, nominally, reduced AST in EAS (β = -0.096; P value = .03), reduced ALP in EUR (β = -2.078; P value = .014), and increased direct bilirubin in EUR (β = 0.071; P value = .032). Sensitivity analyses using genetic instruments derived from circulating PCSK9 protein levels, tissue-specific PCSK9 expression, and HMGCR expression were in alignment, strengthening causal inference.
CONCLUSIONS
We did not find ALT, AST, GGT, or ALP associated with genetically proxied PCSK9 and HMGCR inhibition across ancestries. We identified possible relationships in several ancestries between PCSK9 and increased direct and total bilirubin and between HMGCR and reduced AST. These findings support long-term safety profiles and low hepatotoxic risk of PCSK9 and HMGCR inhibition in diverse populations.
Topics: Humans; Proprotein Convertase 9; Subtilisin; Genome-Wide Association Study; Mendelian Randomization Analysis; Liver; Bilirubin; Lipoproteins, LDL; Cholesterol; Lipids; Hydroxymethylglutaryl CoA Reductases
PubMed: 37703945
DOI: 10.1016/j.jcmgh.2023.09.001 -
Frontiers in Immunology 2023Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause of death is cardiovascular disease (CVD). The levels of total cholesterol... (Review)
Review
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause of death is cardiovascular disease (CVD). The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) in RA decrease especially under hyperinflammatory conditions. It is conflictive with the increased risk of CVD in RA, which is called "lipid paradox". The systemic inflammation may explain this apparent contradiction. The increased systemic proinflammatory cytokines in RA mainly include interleukin-6(IL-6)、interleukin-1(IL-1)and tumor necrosis factor alpha(TNF-α). The inflammation of RA cause changes in the subcomponents and structure of HDL particles, leading to a weakened anti-atherosclerosis function and promoting LDL oxidation and plaque formation. Dysfunctional HDL can further worsen the abnormalities of LDL metabolism, increasing the risk of cardiovascular disease. However, the specific mechanisms underlying lipid changes in RA and increased CVD risk remain unclear. Therefore, this article comprehensively integrates the latest existing literature to describe the unique lipid profile of RA, explore the mechanisms of lipid changes, and investigate the impact of lipid changes on cardiovascular disease.
Topics: Humans; Cardiovascular Diseases; Arthritis, Rheumatoid; Inflammation; Cholesterol, LDL; Tumor Necrosis Factor-alpha; Dyslipidemias
PubMed: 37954591
DOI: 10.3389/fimmu.2023.1254753 -
Pharmacological Research Sep 2023The subendothelial retention of apolipoprotein B (apoB)-containing lipoproteins is a critical step in the initiation of pro-atherosclerotic processes. Recent genetic and...
The subendothelial retention of apolipoprotein B (apoB)-containing lipoproteins is a critical step in the initiation of pro-atherosclerotic processes. Recent genetic and clinical evidence strongly supports the concept that the lipid content of the particles is secondary to the number of circulating atherogenic particles that are trapped within the arterial lumen. Since each low-density lipoproteins (LDL) particle contains one apoB molecule, as do intermediate density lipoprotein (IDL) and very low-density lipoprotein (VLDL) particles, apoB level represents the total number of atherogenic lipoproteins, which is independent of particle density, and not affected by the heterogeneity of particle cholesterol content (clinically evaluated by LDL-cholesterol level). From this perspective, apoB is proposed as a better proxy to LDL-cholesterol for assessing atherosclerotic cardiovascular disease risk, especially in specific subgroups of patients, including subjects with diabetes mellitus, with multiple cardiometabolic risk factors (obesity, metabolic syndrome, insulin resistance, and hypertension) and with high triglyceride levels and very low LDL-cholesterol levels. Therefore, given the causal role of LDL-cholesterol in atherosclerotic cardiovascular disease (ASCVD) development, routine measurement of both LDL-cholesterol and apoB is of utmost importance to properly estimate global cardiovascular risk and to determine the 'residual' risk of ASCVD in patients receiving therapy, as well as to monitor therapeutic effectiveness.
Topics: Humans; Apolipoproteins B; Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Risk Assessment; Triglycerides
PubMed: 37517561
DOI: 10.1016/j.phrs.2023.106873 -
Arteriosclerosis, Thrombosis, and... Jul 2023APOA1 and APOB are the structural proteins of high-density lipoprotein and APOB-containing lipoproteins, such as low-density lipoprotein and very low-density... (Review)
Review
APOA1 and APOB are the structural proteins of high-density lipoprotein and APOB-containing lipoproteins, such as low-density lipoprotein and very low-density lipoprotein, respectively. The 4 smaller APOCs (APOC1, APOC2, APOC3, and APOC4) are exchangeable apolipoproteins; they are readily transferred among high-density lipoproteins and APOB-containing lipoproteins. The APOCs regulate plasma triglyceride and cholesterol levels by modulating substrate availability and activities of enzymes interacting with lipoproteins and by interfering with APOB-containing lipoprotein uptake through hepatic receptors. Of the 4 APOCs, APOC3 has been best studied in relation to diabetes. Elevated serum APOC3 levels predict incident cardiovascular disease and progression of kidney disease in people with type 1 diabetes. Insulin suppresses APOC3 levels, and accordingly, elevated APOC3 levels associate with insulin deficiency and insulin resistance. Mechanistic studies in a mouse model of type 1 diabetes have demonstrated that APOC3 acts in the causal pathway of diabetes-accelerated atherosclerosis. The mechanism is likely due to the ability of APOC3 to slow the clearance of triglyceride-rich lipoproteins and their remnants, thereby causing an increased accumulation of atherogenic lipoprotein remnants in lesions of atherosclerosis. Less is known about the roles of APOC1, APOC2, and APOC4 in diabetes.
Topics: Mice; Animals; Apolipoprotein C-II; Diabetes Mellitus, Type 1; Lipoproteins; Triglycerides; Lipoproteins, HDL; Apolipoprotein C-III; Lipoproteins, LDL; Atherosclerosis; Apolipoproteins B; Insulins
PubMed: 37226733
DOI: 10.1161/ATVBAHA.122.318290 -
Blood Sep 2023von Willebrand factor (VWF) mediates primary hemostasis and thrombosis in response to hydrodynamic forces. We previously showed that high shear promoted self-association...
von Willebrand factor (VWF) mediates primary hemostasis and thrombosis in response to hydrodynamic forces. We previously showed that high shear promoted self-association of VWF into hyperadhesive strands, which can be attenuated by high-density lipoprotein (HDL) and apolipoprotein A-I. In this study, we show that low-density lipoprotein (LDL) binds VWF under shear and enhances self-association. Vortexing VWF in tubes resulted in its loss from the solution and deposition onto tube surfaces, which was prevented by HDL. At a stabilizing HDL concentration of 1.2 mg/mL, increasing concentrations of LDL progressively increased VWF loss, the effect correlating with the LDL-to-HDL ratio and not the absolute concentration of the lipoproteins. Similarly, HDL diminished deposition of VWF in a post-in-channel microfluidic device, whereas LDL increased both the rate and extent of strand deposition, with both purified VWF and plasma. Hypercholesterolemic human plasma also displayed accelerated VWF accumulation in the microfluidic device. The initial rate of accumulation correlated linearly with the LDL-to-HDL ratio. In Adamts13-/- and Adamts13-/-LDLR-/- mice, high LDL levels enhanced VWF and platelet adhesion to the myocardial microvasculature, reducing cardiac perfusion, impairing systolic function, and producing early signs of cardiomyopathy. In wild-type mice, high plasma LDL concentrations also increased the size and persistence of VWF-platelet thrombi in ionophore-treated mesenteric microvessels, exceeding the accumulation seen in similarly treated ADAMTS13-deficient mice that did not receive LDL infusion. We propose that targeting the interaction of VWF with itself and with LDL may improve the course of thrombotic microangiopathies, atherosclerosis, and other disorders with defective microvascular circulation.
Topics: Mice; Humans; Animals; von Willebrand Factor; Lipoproteins, LDL; Thrombosis; Hemostasis; Platelet Adhesiveness; ADAMTS13 Protein
PubMed: 37506337
DOI: 10.1182/blood.2023019749 -
BMC Nephrology Oct 2023This study aimed to analyze low-density lipoprotein cholesterol (LDL-C) levels and their relationship with mortality in order to identify the appropriate lipid profile...
BACKGROUND
This study aimed to analyze low-density lipoprotein cholesterol (LDL-C) levels and their relationship with mortality in order to identify the appropriate lipid profile for older Korean hemodialysis patients.
METHODS
We enrolled a total of 2,732 incident hemodialysis patients aged > 70 years from a retrospective cohort of the Korean Society of Geriatric Nephrology from 2010 Jan to 2017 Dec, which included 17 academic hospitals in South Korea. Of these patients, 1,709 were statin-naïve, and 1,014 were analyzed after excluding those with missing LDL-C level data. We used multivariate Cox regression analysis to select risk factors from 20 clinical variables among the LDL-C groups.
RESULTS
The mean age of the entire patient population was 78 years, with no significant differences in age between quartiles Q1 to Q4. However, the proportion of males decreased as the quartiles progressed towards Q4 (p < 0.001). The multivariate Cox regression analysis, which included all participants, showed that low LDL-C levels were associated with all-cause mortality. In the final model, compared to Q1, the hazard ratios (95% confidence interval) were 0.77 (0.620-0.972; p = 0.027), 0.85 (0.676-1.069; p = 0.166), and 0.65 (0.519-0.824; p < 0.001) for Q2, Q3, and Q4, respectively, after adjusting for covariates, such as conventional and age-specific risk factors. The final model demonstrated that all-cause mortality increased as LDL-C levels decreased, as confirmed by a restrictive cubic spline plot.
CONCLUSIONS
In older hemodialysis patients who had not previously received dyslipidemia treatment, elevated LDL-C levels were not associated with increased all-cause mortality. Intriguingly, lower LDL-C levels appear to be associated with an unfavorable effect on all-cause mortality among high-risk hemodialysis patients.
Topics: Male; Humans; Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Retrospective Studies; Renal Dialysis; Risk Factors
PubMed: 37784041
DOI: 10.1186/s12882-023-03337-5 -
Current Opinion in Lipidology Oct 2023Advances in single cell techniques revealed a remarkable diversity in macrophage gene expression profiles in atherosclerosis. However, the diversity of functional... (Review)
Review
PURPOSE OF REVIEW
Advances in single cell techniques revealed a remarkable diversity in macrophage gene expression profiles in atherosclerosis. However, the diversity of functional processes at the macrophage plasma membrane remains less studied. This review summarizes recent advances in characterization of lipid rafts, where inflammatory receptors assemble, in macrophages that undergo reprogramming in atherosclerotic lesions and in vitro under conditions relevant to the development of atherosclerosis.
RECENT FINDINGS
The term inflammarafts refers to enlarged lipid rafts with increased cholesterol content, hosting components of inflammatory receptor complexes assembled in close proximity, including TLR4-TLR4, TLR2-TLR1 and TLR2-CD36 dimers. Macrophages decorated with inflammarafts maintain chronic inflammatory gene expression and are primed to an augmented response to additional inflammatory stimuli. In mouse atherosclerotic lesions, inflammarafts are expressed primarily in nonfoamy macrophages and less in lipid-laden foam cells. This agrees with the reported suppression of inflammatory programs in foam cells. In contrast, nonfoamy macrophages expressing inflammarafts are the major inflammatory population in atherosclerotic lesions. Discussed are emerging reports that help understand formation and persistence of inflammarafts and the potential of inflammarafts as a novel therapeutic target.
SUMMARY
Chronic maintenance of inflammarafts in nonfoamy macrophages serves as an effector mechanism of inflammatory macrophage reprogramming in atherosclerosis.
Topics: Animals; Mice; Toll-Like Receptor 4; Toll-Like Receptor 2; Lipoproteins, LDL; Macrophages; Atherosclerosis; Foam Cells; Plaque, Atherosclerotic
PubMed: 37527160
DOI: 10.1097/MOL.0000000000000888 -
MMW Fortschritte Der Medizin Jul 2023
Topics: Humans; Diabetes Mellitus; Lipoproteins, LDL
PubMed: 37420054
DOI: 10.1007/s15006-023-2808-0