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Atherosclerosis May 2024Previous studies have derived and validated an HDL apolipoproteomic score (pCAD) that predicts coronary artery disease (CAD) risk. However, the associations between pCAD...
BACKGROUND AND AIMS
Previous studies have derived and validated an HDL apolipoproteomic score (pCAD) that predicts coronary artery disease (CAD) risk. However, the associations between pCAD and markers of cardiometabolic health in healthy adults are not known, nor are the effects of regular exercise on pCAD.
METHODS
A total of 641 physically inactive adults free of cardiovascular disease from the HERITAGE Family Study completed 20 weeks of exercise training. The pCAD index (range 0-100) was calculated using measurements of apolipoproteins A-I, C-I, C-II, C-III, and C-IV from ApoA-I-tagged serum (higher index = higher CAD risk). The associations between pCAD index and cardiometabolic traits at baseline and their training responses were assessed with Spearman correlation and general linear models. A Bonferroni correction of p < 8.9 × 10 was used to determine statistical significance.
RESULTS
The mean ± SD baseline pCAD index was 29 ± 32, with 106 (16.5 %) participants classified as high CAD risk. At baseline, pCAD index was positively associated with blood pressure, systemic inflammation, and body composition. HDL size, VOmax, and HDL-C were negatively associated with pCAD index at baseline. Of those classified as high CAD risk at baseline, 52 (49 %) were reclassified as normal risk after training. Following training, pCAD index changes were inversely correlated (p < 1.4 × 10) with changes in HDL-C, HDL size, and LDL size.
CONCLUSIONS
A higher pCAD index was associated with a worse cardiometabolic profile at baseline but improved with regular exercise. The results from this study highlight the potential role of HDL apolipoproteins as therapeutic targets for lifestyle interventions, particularly in high-risk individuals.
PubMed: 38823353
DOI: 10.1016/j.atherosclerosis.2024.117587 -
PLoS Computational Biology May 2024Lecithin:cholesterol acyltransferase (LCAT) exhibits α-activity on high-density and β-activity on low-density lipoproteins. However, the molecular determinants...
Systematic evaluation of lecithin:cholesterol acyltransferase binding sites in apolipoproteins via peptide based nanodiscs: regulatory role of charged residues at positions 4 and 7.
Lecithin:cholesterol acyltransferase (LCAT) exhibits α-activity on high-density and β-activity on low-density lipoproteins. However, the molecular determinants governing LCAT activation by different apolipoproteins remain elusive. Uncovering these determinants would offer the opportunity to design and explore advanced therapies against dyslipidemias. Here, we have conducted coarse-grained and all-atom molecular dynamics simulations of LCAT with nanodiscs made with α-helical amphiphilic peptides either derived from apolipoproteins A1 and E (apoA1 and apoE) or apoA1 mimetic peptide 22A that was optimized to activate LCAT. This study aims to explore what drives the binding of peptides to our previously identified interaction site in LCAT. We hypothesized that this approach could be used to screen for binding sites of LCAT in different apolipoproteins and would provide insights to differently localized LCAT activities. Our screening approach was able to discriminate apoA1 helixes 4, 6, and 7 as key contributors to the interaction with LCAT supporting the previous research data. The simulations provided detailed molecular determinants driving the interaction with LCAT: the formation of hydrogen bonds or salt bridges between peptides E4 or D4 and LCAT S236 or K238 residues. Additionally, salt bridging between R7 and D73 was observed, depending on the availability of R7. Expanding our investigation to diverse plasma proteins, we detected novel LCAT binding helixes in apoL1, apoB100, and serum amyloid A. Our findings suggest that the same binding determinants, involving E4 or D4 -S236 and R7-D73 interactions, influence LCAT β-activity on low-density lipoproteins, where apoE and or apoB100 are hypothesized to interact with LCAT.
Topics: Phosphatidylcholine-Sterol O-Acyltransferase; Binding Sites; Molecular Dynamics Simulation; Apolipoproteins; Apolipoprotein A-I; Humans; Peptides; Nanostructures; Protein Binding; Apolipoproteins E
PubMed: 38805510
DOI: 10.1371/journal.pcbi.1012137 -
Journal of Lipid Research Jun 2024Hypertriglyceridemia (HTG) is a common cardiovascular risk factor characterized by elevated triglyceride (TG) levels. Researchers have assessed the genetic factors that...
Hypertriglyceridemia (HTG) is a common cardiovascular risk factor characterized by elevated triglyceride (TG) levels. Researchers have assessed the genetic factors that influence HTG in studies focused predominantly on individuals of European ancestry. However, relatively little is known about the contribution of genetic variation of HTG in people of African ancestry (AA), potentially constraining research and treatment opportunities. Our objective was to characterize genetic profiles among individuals of AA with mild-to-moderate HTG and severe HTG versus those with normal TGs by leveraging whole-genome sequencing data and longitudinal electronic health records available in the All of Us program. We compared the enrichment of functional variants within five canonical TG metabolism genes, an AA-specific polygenic risk score for TGs, and frequencies of 145 known potentially causal TG variants between HTG patients and normal TG among a cohort of AA patients (N = 15,373). Those with mild-to-moderate HTG (N = 342) and severe HTG (N ≤ 20) were more likely to carry APOA5 p.S19W (odds ratio = 1.94, 95% confidence interval = [1.48-2.54], P = 1.63 × 10 and OR = 3.65, 95% confidence interval: [1.22-10.93], P = 0.02, respectively) than those with normal TG. They were also more likely to have an elevated (top 10%) polygenic risk score, elevated carriage of potentially causal variant alleles, and carry any genetic risk factor. Alternative definitions of HTG yielded comparable results. In conclusion, individuals of AA with HTG were enriched for genetic risk factors compared to individuals with normal TGs.
Topics: Humans; Triglycerides; Male; Female; Hypertriglyceridemia; Middle Aged; United States; Apolipoprotein A-V; Black People; Adult; Black or African American
PubMed: 38795861
DOI: 10.1016/j.jlr.2024.100569 -
Current Problems in Cardiology Aug 2024CSL-112, a recombinant human apolipoprotein A-I, holds promise for treating atherosclerotic disease by promoting reverse cholesterol transport. This review evaluates the... (Review)
Review
CSL-112, a recombinant human apolipoprotein A-I, holds promise for treating atherosclerotic disease by promoting reverse cholesterol transport. This review evaluates the current evidence on CSL-112's impact on atherosclerotic disease. A search identified studies investigating the effect of CSL-112 on apolipoprotein A-I levels, cholesterol efflux capacity, clinical outcomes, safety profile, pharmacokinetics, pharmacodynamics, and subgroup analysis in patients with atherosclerotic disease. All nine studies consistently demonstrated a dose-dependent increase in apolipoprotein A-I levels following CSL-112 administration. Most studies also reported a corresponding rise in cholesterol efflux capacity. However, the AEGIS-II trial, the largest study to date, did not show a statistically significant reduction in major adverse cardiovascular events in patients with acute myocardial infarction treated with CSL-112 compared to placebo. While some smaller studies suggested potential benefits, particularly in stable atherosclerotic disease, their limitations in size and duration necessitate further investigation. CSL-112 appeared to be generally well-tolerated, with mostly mild or moderate adverse events reported. However, the AEGIS-II trial identified a higher incidence of hypersensitivity reactions in the CSL-112 group, requiring further exploration. CSL-112 demonstrates promise in raising apolipoprotein A-I levels and enhancing cholesterol efflux capacity, potentially promoting reverse cholesterol transport. However, its clinical efficacy for atherosclerotic disease remains unclear. Larger, well-designed trials with longer follow-up periods are necessary to definitively establish its clinical benefit and safety profile before widespread clinical use can be considered. Future research should also explore deeper into the pharmacokinetic and pharmacodynamic profile of CSL-112 and explore its efficacy and safety in different patient subgroups.
Topics: Humans; Atherosclerosis; Apolipoprotein A-I; Recombinant Proteins; Treatment Outcome; Cholesterol; Lipoproteins, HDL
PubMed: 38795809
DOI: 10.1016/j.cpcardiol.2024.102680 -
Nutrients May 2024Previous studies have shown encouraging results regarding the efficacy and safety of nutraceuticals, such as "red yeast rice (RYR) extract", on reducing... (Meta-Analysis)
Meta-Analysis Review
Safety and Efficacy of the Consumption of the Nutraceutical "Red Yeast Rice Extract" for the Reduction of Hypercholesterolemia in Humans: A Systematic Review and Meta-Analysis.
Previous studies have shown encouraging results regarding the efficacy and safety of nutraceuticals, such as "red yeast rice (RYR) extract", on reducing hypercholesterolemia in humans. A systematic review and meta-analysis was conducted from January 2012 to May 2022. The search was strictly focused on clinical trials that examined the association between RYR extract consumption and parameters of the lipid profile in humans. Fourteen double-blinded clinical trials were identified. The interventions lasted 4-24 weeks. In most studies, there was one intervention group and one control group. RYR extract consumption statistically significantly reduced total cholesterol (mean absolute reduction: 37.43 mg/dL; 95% confidence interval [CI]: -47.08, -27.79) and low-density lipoprotein cholesterol (LDL-C; mean absolute reduction: 35.82 mg/dL; 95% CI: -43.36, -28.29), but not high-density lipoprotein cholesterol, triglycerides and apolipoproteins A-I and B. As regards the safety, RYR extract was considered a safe choice with neither threatening nor frequent side effects. The consumption of RYR extract by people with hypercholesterolemia was associated with statistically significant reduction in total cholesterol and LDL-C, whereas it was not associated with an increase in life-threatening side effects. Further research on specific subpopulations and outcomes could establish a consensus on determining the clinical benefits and potential risks, if any, of this nutraceutical.
Topics: Adult; Humans; Middle Aged; Anticholesteremic Agents; Biological Products; Cholesterol; Cholesterol, LDL; Dietary Supplements; Hypercholesterolemia; Treatment Outcome; Young Adult; Aged; Aged, 80 and over
PubMed: 38794691
DOI: 10.3390/nu16101453 -
International Journal of Molecular... May 2024CIGB-258, a 3 kDa peptide from heat shock protein 60, exhibits synergistic anti-inflammatory activity with apolipoprotein A-I (apoA-I) in reconstituted high-density...
Synergistic Anti-Inflammatory Activity of Lipid-Free Apolipoprotein (apo) A-I and CIGB-258 in Acute-Phase Zebrafish via Stabilization of the apoA-I Structure to Enhance Anti-Glycation and Antioxidant Activities.
CIGB-258, a 3 kDa peptide from heat shock protein 60, exhibits synergistic anti-inflammatory activity with apolipoprotein A-I (apoA-I) in reconstituted high-density lipoproteins (rHDLs) via stabilization of the rHDL structure. This study explored the interactions between CIGB-258 and apoA-I in the lipid-free state to assess their synergistic effects in the structural and functional enhancement of apoA-I and HDL. A co-treatment of lipid-free apoA-I and CIGB-258 inhibited the cupric ion-mediated oxidation of low-density lipoprotein (LDL) and a lowering of oxidized species in the dose-responsive manner of CIGB-258. The co-presence of CIGB-258 caused a blue shift in the wavelength of maximum fluorescence (WMF) of apoA-I with protection from proteolytic degradation. The addition of apoA-I:CIGB-258, with a molar ratio of 1:0.1, 1:0.5, and 1:1, to HDL and HDL remarkably enhanced the antioxidant ability against LDL oxidation up to two-fold higher than HDL alone. HDL-associated paraoxonase activities were elevated up to 28% by the co-addition of apoA-I and CIGB-258, which is linked to the suppression of Cu-mediated HDL oxidation with the slowest electromobility. Isothermal denaturation by a urea treatment showed that the co-presence of CIGB-258 attenuated the exposure of intrinsic tryptophan (Trp) and increased the mid-points of denaturation from 2.33 M for apoA-I alone to 2.57 M for an apoA-I:CIGB-258 mixture with a molar ratio of 1:0.5. The addition of CIGB-258 to apoA-I protected the carboxymethyllysine (CML)-facilitated glycation of apoA-I with the prevention of Trp exposure. A co-treatment of apoA-I and CIGB-258 synergistically safeguarded zebrafish embryos from acute death by CML-toxicity, suppressing oxidative stress and apoptosis. In adult zebrafish, the co-treatment of apoA-I+CIGB-258 exerted the highest anti-inflammatory activity with a higher recovery of swimming ability and survivability than apoA-I alone or CIGB-258 alone. A co-injection of apoA-I and CIGB-258 led to the lowest infiltration of neutrophils and interleukin (IL)-6 generation in hepatic tissue, with the lowest serum triglyceride, aspartate transaminase, and alanine transaminase levels in plasma. In conclusion, the co-presence of CIGB-258 ameliorated the beneficial functionalities of apoA-I, such as antioxidant and anti-glycation activities, by enhancing the structural stabilization and protection of apoA-I. The combination of apoA-I and CIGB-258 synergistically enforced the anti-inflammatory effect against CML toxicity in embryos and adult zebrafish.
Topics: Apolipoprotein A-I; Animals; Zebrafish; Antioxidants; Anti-Inflammatory Agents; Lipoproteins, HDL; Lipoproteins, LDL; Oxidation-Reduction; Drug Synergism
PubMed: 38791598
DOI: 10.3390/ijms25105560 -
ELife May 2024Severe dengue infections are characterized by endothelial dysfunction shown to be associated with the secreted nonstructural protein 1 (sNS1), making it an attractive...
Severe dengue infections are characterized by endothelial dysfunction shown to be associated with the secreted nonstructural protein 1 (sNS1), making it an attractive vaccine antigen and biotherapeutic target. To uncover the biologically relevant structure of sNS1, we obtained infection-derived sNS1 (isNS1) from dengue virus (DENV)-infected Vero cells through immunoaffinity purification instead of recombinant sNS1 (rsNS1) overexpressed in insect or mammalian cell lines. We found that isNS1 appeared as an approximately 250 kDa complex of NS1 and ApoA1 and further determined the cryoEM structures of isNS1 and its complex with a monoclonal antibody/Fab. Indeed, we found that the major species of isNS1 is a complex of the NS1 dimer partially embedded in a high-density lipoprotein (HDL) particle. Crosslinking mass spectrometry studies confirmed that the isNS1 interacts with the major HDL component ApoA1 through interactions that map to the NS1 wing and hydrophobic domains. Furthermore, our studies demonstrated that the sNS1 in sera from DENV-infected mice and a human patient form a similar complex as isNS1. Our results report the molecular architecture of a biological form of sNS1, which may have implications for the molecular pathogenesis of dengue.
Topics: Viral Nonstructural Proteins; Animals; Dengue Virus; Chlorocebus aethiops; Mice; Humans; Lipoproteins, HDL; Vero Cells; Dengue; Apolipoprotein A-I; Protein Multimerization; Cryoelectron Microscopy
PubMed: 38787378
DOI: 10.7554/eLife.90762 -
Journal of Clinical Lipidology 2024Increased cholesterol-rich, low-density, non-calcified atheromas as assessed by computer coronary tomography angiography analyses have been shown to predict myocardial... (Review)
Review
Increased cholesterol-rich, low-density, non-calcified atheromas as assessed by computer coronary tomography angiography analyses have been shown to predict myocardial infarction significantly better than coronary artery calcium score or the presence of obstructive coronary artery disease (CAD) as evaluated with standard coronary angiography. Low serum high-density lipoprotein (HDL) cholesterol values are an independent risk factor for CAD. Very small, lipid-poor preβ-1 HDL particles have been shown to be most effective in promoting cellular cholesterol efflux. HDL infusions have been documented to reduce aortic atherosclerosis in cholesterol-fed animal models. However, human studies using infusions of either the HDL mimetic containing recombinant apolipoprotein (apo) A-I Milano or Cerenis Compound-001 with native recombinant apoA-I have been mainly negative in promoting coronary atherosclerosis progression as assessed by intravascular ultrasound. In contrast, a study using 7 weekly infusions of autologous delipidated HDL in six homozygous familial hypercholesterolemic patients was effective in promoting significant regression of low-density non-calcified coronary atheroma regression as assessed by computed coronary angiography. This therapy has received Food and Drug Administration approval. Commonwealth Serum Laboratories has carried out a large clinical endpoint trial using an HDL complex (native apoA-I with phospholipid), and the results were negative. Our purpose is to review animal and human studies using various forms of HDL infusion therapy to promote regression of atherosclerosis. In our view, differences in results may be due to: 1) the HDL preparations used, 2) the subjects studied, and 3) the methods used to assess coronary atherosclerosis.
Topics: Humans; Animals; Lipoproteins, HDL; Coronary Artery Disease; Apolipoprotein A-I
PubMed: 38782655
DOI: 10.1016/j.jacl.2024.01.009 -
Veterinary Microbiology Jul 2024Glaesserella parasuis (G. parasuis) is the causative agent of porcine Glässer's disease, resulting in high mortality rates in pigs due to excessive inflammation-induced...
Glaesserella parasuis (G. parasuis) is the causative agent of porcine Glässer's disease, resulting in high mortality rates in pigs due to excessive inflammation-induced tissue damage. Previous studies investigating the protective effects of G. parasuis vaccination indicated a possible role of ApoA1 in reflecting disease progression following G. parasuis infection. However, the mechanisms of ApoA1 expression and its role in these infections are not well understood. In this investigation, newborn porcine tracheal (NPTr) epithelial cells infected with G. parasuis were used to elucidate the molecular mechanism and role of ApoA1. The study revealed that the AMPK pathway activation inhibited ApoA1 expression in NPTr cells infected with G. parasuis for the first time. Furthermore, Egr1 was identified as a core transcription factor regulating ApoA1 expression using a CRISPR/Cas9-based system. Importantly, it was discovered that APOA1 protein significantly reduced apoptosis, pyroptosis, necroptosis, and inflammatory factors induced by G. parasuis in vivo. These findings not only enhance our understanding of ApoA1 in response to bacterial infections but also highlight its potential in mitigating tissue damage caused by G. parasuis infection.
Topics: Animals; Swine; Apolipoprotein A-I; Signal Transduction; Early Growth Response Protein 1; Haemophilus parasuis; Swine Diseases; AMP-Activated Protein Kinases; Haemophilus Infections; Epithelial Cells; Gene Expression Regulation; Trachea; Apoptosis; Animals, Newborn
PubMed: 38776767
DOI: 10.1016/j.vetmic.2024.110106 -
Journal of the American Chemical Society Jun 2024For cationic nanoparticles, the spontaneous nanoparticle-protein corona formation and aggregation in biofluids can trigger unexpected biological reactions. Herein, we...
For cationic nanoparticles, the spontaneous nanoparticle-protein corona formation and aggregation in biofluids can trigger unexpected biological reactions. Herein, we present a biomimetic strategy for camouflaging the cationic peptide/siRNA nanocomplex (P/Si) with single or dual proteins, which exploits the unique properties of endogenous proteins and stabilizes the cationic P/Si complex for safe and targeted delivery. An in-depth study of the P/Si protein corona (P/Si-PC) formation and protein binding was conducted. The results provided insights into the biochemical and toxicological properties of cationic nanocomplexes and the rationales for engineering biomimetic protein camouflages. Based on this, the human serum albumin (HSA) and apolipoprotein AI (Apo-AI) ranked within the top 20 abundant protein species of P/Si-PC were selected to construct biomimetic HSA-dressed P/Si (P/Si@HSA) and dual protein (HSA and Apo-AI)-dressed P/Si (P/Si@HSA_Apo), given that the dual-protein camouflage plays complementary roles in efficient delivery. A branched cationic peptide (b-HKR) was tailored for siRNA delivery, and their nanocomplexes, including the cationic P/Si and biomimetic protein-dressed P/Si, were produced by a precise microfluidic technology. The biomimetic anionic protein camouflage greatly enhanced P/Si biostability and biocompatibility, which offers a reliable strategy for overcoming the limitation of applying cationic nanoparticles in biofluids and systemic delivery.
Topics: Humans; RNA, Small Interfering; Peptides; Biomimetic Materials; Nanoparticles; Serum Albumin, Human; Protein Engineering; Apolipoprotein A-I; Protein Corona; Biomimetics
PubMed: 38773940
DOI: 10.1021/jacs.4c00691