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Oxidative Medicine and Cellular... 2020Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular... (Review)
Review
Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular events contributing to the most considerable number of morbidity and mortality worldwide. Factors like cellular senescence, genetics, clonal haematopoiesis, sedentary lifestyle-induced obesity, or diabetes mellitus upsurge the tendency of atherosclerosis and are foremost pioneers to definitive transience. Accumulation of oxidized low-density lipoproteins (Ox-LDLs) in the tunica intima triggers the onset of this disease. In the later period of progression, the build-up plaques rupture ensuing thrombosis (completely blocking the blood flow), causing myocardial infarction, stroke, and heart attack, all of which are common atherosclerotic cardiovascular events today. The underlying mechanism is very well elucidated in literature but the therapeutic measures remains to be unleashed. Researchers tussle to demonstrate a clear understanding of treating mechanisms. A century of research suggests that lowering LDL, statin-mediated treatment, HDL, and lipid-profile management should be of prime interest to retard atherosclerosis-induced deaths. We shall brief the Ox-LDL-induced atherogenic mechanism and the treating measures in line to impede the development and progression of atherosclerosis.
Topics: Antioxidants; Atherosclerosis; Endothelium; Humans; Lipoproteins, LDL; Macrophages; Oxidative Stress; Reactive Oxygen Species; Risk Factors
PubMed: 33014272
DOI: 10.1155/2020/5245308 -
Trends in Cardiovascular Medicine Jan 2019We provide an up-to-date overview of current topics surrounding oxidized low-density lipoprotein (oxLDL) and its related antibodies in the quest to better identify the... (Review)
Review
We provide an up-to-date overview of current topics surrounding oxidized low-density lipoprotein (oxLDL) and its related antibodies in the quest to better identify the individuals at risk of cardiovascular disease and atherosclerotic plaques with unfavorable characteristics. We discuss the potential of oxLDL and anti-oxLDL antibodies as serum biomarkers of cardiovascular disease and emerging studies examining the targeting of arterial oxLDL for imaging and therapeutic delivery.
Topics: Animals; Antibodies; Arteries; Atherosclerosis; Biomarkers; Humans; Immunization; Lipoproteins, LDL; Molecular Imaging; Plaque, Atherosclerotic; Predictive Value of Tests; Prognosis; Vaccines
PubMed: 29934015
DOI: 10.1016/j.tcm.2018.05.010 -
Cardiovascular Research Feb 2022The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow's triad of hypercoagulability, structural... (Review)
Review
The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow's triad of hypercoagulability, structural abnormalities, and blood stasis. More recently, there is emerging evidence that lipoproteins are implicated in this process, beyond their traditional role in atherosclerosis. In this review, we provide an overview of the various lipoproteins and explore the association between lipoproteins and AF, the effects of lipoproteins on haemostasis, and the potential contribution of lipoproteins to thrombogenesis in AF. There are several types of lipoproteins based on size, lipid composition, and apolipoprotein category, namely: chylomicrons, very low-density lipoprotein, low-density lipoprotein (LDL), intermediate-density lipoprotein, and high-density lipoprotein. Each of these lipoproteins may contain numerous lipid species and proteins with a variety of different functions. Furthermore, the lipoprotein particles may be oxidized causing an alteration in their structure and content. Of note, there is a paradoxical inverse relationship between total cholesterol and LDL cholesterol (LDL-C) levels, and incident AF. The mechanism by which this occurs may be related to the stabilizing effect of cholesterol on myocardial membranes, along with its role in inflammation. Overall, specific lipoproteins may interact with haemostatic pathways to promote excess platelet activation and thrombin generation, as well as inhibiting fibrinolysis. In this regard, LDL-C has been shown to be an independent risk factor for thromboembolic events in AF. The complex relationship between lipoproteins, thrombosis and AF warrants further research with an aim to improve our knowledge base and contribute to our overall understanding of lipoprotein-mediated thrombosis.
Topics: Atrial Fibrillation; Cholesterol, LDL; Humans; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Thrombosis
PubMed: 33483737
DOI: 10.1093/cvr/cvab017 -
Journal of the American College of... Jan 2023It is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD).
BACKGROUND
It is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD).
OBJECTIVES
This study tested the hypothesis that elevated LDL triglycerides are associated with an increased risk of ASCVD and of each ASCVD component individually.
METHODS
The study investigators used the Copenhagen General Population Study, which measured LDL triglycerides in 38,081 individuals with a direct automated assay (direct LDL triglycerides) and in another 30,208 individuals with nuclear magnetic resonance (NMR) spectroscopy (NMR LDL triglycerides). Meta-analyses aggregated the present findings with previously reported results.
RESULTS
During a median follow-up of 3.0 and 9.2 years, respectively, 872 and 5,766 individuals in the 2 cohorts received a diagnosis of ASCVD. Per 0.1 mmol/L (9 mg/dL) higher direct LDL triglycerides, HRs were 1.26 (95% CI: 1.17-1.35) for ASCVD, 1.27 (95% CI: 1.16-1.39) for ischemic heart disease, 1.28 (95% CI: 1.11-1.48) for myocardial infarction, 1.22 (95% CI: 1.08-1.38) for ischemic stroke, and 1.38 (95% CI: 1.21-1.58) for peripheral artery disease. Corresponding HRs for NMR LDL triglycerides were 1.26 (95% CI: 1.20-1.33), 1.33 (95% CI: 1.25-1.41), 1.41 (95% CI: 1.31-1.52), 1.13 (95% CI: 1.05-1.23), and 1.26 (95% CI: 1.10-1.43), respectively. The foregoing results were not entirely statistically explained by apolipoprotein B levels. In meta-analyses for the highest quartile vs the lowest quartile of LDL triglycerides, random-effects risk ratios were 1.50 (95% CI: 1.35-1.66) for ASCVD (4 studies; 71,526 individuals; 8,576 events), 1.62 (95% CI: 1.37-1.93) for ischemic heart disease (6 studies; 107,538 individuals; 9,734 events), 1.30 (95% CI: 1.13-1.49) for ischemic stroke (4 studies; 78,026 individuals; 4,273 events), and 1.53 (95% CI: 1.29-1.81) for peripheral artery disease (4 studies; 107,511 individuals; 1,848 events).
CONCLUSIONS
Elevated LDL triglycerides were robustly associated with an increased risk of ASCVD and of each ASCVD component individually in 2 prospective cohort studies and in meta-analyses of previous and present studies combined.
Topics: Humans; Atherosclerosis; Cholesterol, LDL; Hypertriglyceridemia; Ischemic Stroke; Myocardial Ischemia; Peripheral Arterial Disease; Prospective Studies; Risk Factors; Triglycerides; Lipoproteins, LDL
PubMed: 36631208
DOI: 10.1016/j.jacc.2022.10.019 -
Nature Communications May 2023Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein...
Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia.
Topics: Animals; Gene Editing; Homozygous Familial Hypercholesterolemia; Clustered Regularly Interspaced Short Palindromic Repeats; Nanoparticles; Liver; Receptors, LDL; Lipoproteins, LDL
PubMed: 37188660
DOI: 10.1038/s41467-023-37465-1 -
Advances in Experimental Medicine and... 2022Sphingolipids and cholesterol are two lipid partners on cellular membranes where they form specific microdomains, named lipid rafts, which mediate specific cell...
Sphingolipids and cholesterol are two lipid partners on cellular membranes where they form specific microdomains, named lipid rafts, which mediate specific cell functions. Sphingomyelin (SM) is one of the major sphingolipids. SM and free cholesterol are also two key lipids on the monolayer of plasma lipoproteins, including chylomicron, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), which participate in lipid transport in the circulation. Thus, sphingolipids and cholesterol play a fundamental role in cell membrane structure and blood lipid transport. In this chapter we will discuss the relationship between both lipids, on the cell membrane and in the circulation, as well as the impact of such relationship in the development of metabolic diseases.
Topics: Cholesterol; Lipids; Lipoproteins; Lipoproteins, LDL; Sphingolipids
PubMed: 35503170
DOI: 10.1007/978-981-19-0394-6_1 -
Cell Death & Disease Sep 2022Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is...
Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known molecule that participates in cellular defense against oxidative stress. Utilizing luciferase reporter assay from 379 natural products, we reported here that Ginsenoside Rb1 played a dual role in inhibiting Kelch-like ECH-associated protein 1 (Keap1) and p47 luciferase reporter activities. In endothelial cells (ECs), Rb1 pretreatment enhanced cell viability, reduced oxidative stress, inflammation, endothelial-mesenchymal transition (EndMT), and apoptosis, as well as ameliorated mitochondrial quality following oxidized low-density lipoprotein (ox-LDL) plus high glucose (HG) challenge. Rb1 directly bound to Keap1 and promoted its ubiquitination and proteasomal degradation dependent on lysine residues (K108, K323, and K551) by recruiting the E3 ligase synovial apoptosis inhibitor 1 (SYVN1), leading to Nrf2 dissociation from Keap1, Nrf2 nuclear translocation, Nrf2/PGC-1α complex formation. We further identified that Rb1 could bind to p47 and reduce its phosphorylation and membrane translocation, thereby disrupting the assembly of the NOX2 complex. Importantly, Rb1-mediated preservation of cytoplasmic p47 stabilized and contributed to Nrf2 activation. Additionally, we revealed that Rb1 reduced aortic atherosclerotic plaque formation along with reductions in oxidative stress and inflammatory response in streptozotocin (STZ)-induced ApoE mice, but not in ApoE mice with deficiency of Nrf2 and PGC-1α. Collectively, we demonstrated that Rb1, which directly targeted Keap1 and p47 in ECs, may be an attractive candidate for the treatment of atherosclerosis in diabetes.
Topics: Animals; Mice; Apolipoproteins E; Atherosclerosis; Biological Products; Diabetes Mellitus; Endothelial Cells; Ginsenosides; Glucose; Kelch-Like ECH-Associated Protein 1; Lipoproteins, LDL; Luciferases; Lysine; NF-E2-Related Factor 2; Oxidative Stress; Streptozocin; Ubiquitin-Protein Ligases
PubMed: 36163178
DOI: 10.1038/s41419-022-05274-x -
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 -
Journal of Thrombosis and Haemostasis :... Mar 2018
Topics: Animals; Blood Coagulation; Editorial Policies; Fibrinolysis; Hemostasis; Humans; Inflammation; Lipoproteins, LDL; Mice; Periodicals as Topic; Staphylococcus aureus; Thrombosis
PubMed: 29442442
DOI: 10.1111/jth.13965 -
Drug Delivery Dec 2021Native nanostructured lipoproteins such as low- and high-density lipoproteins (LDL and HDL) are powerful tools for the targeted delivery of drugs and imaging agents.... (Review)
Review
Native nanostructured lipoproteins such as low- and high-density lipoproteins (LDL and HDL) are powerful tools for the targeted delivery of drugs and imaging agents. While the cellular recognition of well-known HDL-based carriers occurs via interactions with an HDL receptor, the selective delivery and uptake of LDL particles by target cells are more complex. The most well-known mode of LDL-based delivery is via the interaction between apolipoprotein B (Apo-B) - the main protein of LDL - and the low-density lipoprotein receptor (LDLR). LDLR is expressed in the liver, adipocytes, and macrophages, and thus selectively delivers LDL carriers to these cells and tissues. Moreover, the elevated expression of LDLR in tumor cells indicates a role for LDL in the targeted delivery of chemotherapy drugs. In addition, chronic inflammation associated with hypercholesterolemia (i.e., high levels of endogenous LDL) can be abated by LDL carriers, which outcompete the deleterious oxidized LDL for uptake by macrophages. In this case, synthetic LDL nanocarriers act as 'eat-me' signals and exploit mechanisms of native LDL uptake for targeted drug delivery and imaging. Lastly, recent studies have shown that the delivery of LDL-based nanocarriers to macrophages via fluid-phase pinocytosis is a promising tool for atherosclerosis imaging. Hence, the present review summarizes the use of natural and synthetic LDL-based carriers for drug delivery and imaging and discusses various mechanisms of targeting.
Topics: Animals; Atherosclerosis; Drug Carriers; Humans; Hypercholesterolemia; Lipoproteins, HDL; Lipoproteins, LDL; Macrophages; Nanomedicine; Receptors, Lipoprotein
PubMed: 33594923
DOI: 10.1080/10717544.2021.1886199