-
Blood Advances Apr 2023Low-density lipoprotein (LDL) contributes to atherogenesis and cardiovascular disease through interactions with peripheral blood cells, especially platelets. However,...
Low-density lipoprotein (LDL) contributes to atherogenesis and cardiovascular disease through interactions with peripheral blood cells, especially platelets. However, mechanisms by which LDL affects platelet activation and atherothrombosis, and how to best therapeutically target and safely prevent such responses remain unclear. Here, we investigate how oxidized low-density lipoprotein (oxLDL) enhances glycoprotein VI (GPVI)-mediated platelet hemostatic and procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-enhanced platelet procoagulant activity ex vivo. Human platelets were treated with oxLDL and the GPVI-specific agonist, crosslinked collagen-related peptide, and assayed for hemostatic and procoagulant responses in the presence of inhibitors of purinergic receptors (P2YR), cyclooxygenase (COX), and tyrosine kinases. Ex vivo, oxLDL enhanced GPVI-mediated platelet dense granule secretion, α-granule secretion, integrin activation, thromboxane generation and aggregation, as well as procoagulant phosphatidylserine exposure and fibrin generation. Studies of washed human platelets, as well as platelets from mouse and nonhuman primate models of hyperlipidemia, further determined that P2YR antagonists (eg, ticagrelor) and Bruton tyrosine kinase inhibitors (eg, ibrutinib) reduced oxLDL-mediated platelet responses and procoagulant activity, whereas COX inhibitors (eg, aspirin) had no significant effect. Together, our results demonstrate that oxLDL enhances GPVI-mediated platelet procoagulant activity in a manner that may be more effectively reduced by P2YR antagonists and tyrosine kinase inhibitors compared with COX inhibitors.
Topics: Humans; Mice; Animals; Platelet Aggregation Inhibitors; Tyrosine Kinase Inhibitors; Lipoproteins, LDL; Hemostatics
PubMed: 36219587
DOI: 10.1182/bloodadvances.2022007169 -
JACC. Cardiovascular Imaging Aug 2022
Topics: Coronary Artery Disease; Humans; Lipoproteins, LDL; Molecular Imaging; Optical Imaging; Plaque, Atherosclerotic; Predictive Value of Tests
PubMed: 35926906
DOI: 10.1016/j.jcmg.2022.04.013 -
Biochimica Et Biophysica Acta.... Dec 2019Unhealthy Western-type diet and physical inactivity are highly associated with the current obesity epidemic and its related metabolic diseases such as atherosclerosis... (Review)
Review
Unhealthy Western-type diet and physical inactivity are highly associated with the current obesity epidemic and its related metabolic diseases such as atherosclerosis and non-alcoholic steatohepatitis. In addition, increasing evidence indicates that obesity is also a major risk factor for several types of common cancers. Recent studies have provided correlative support that disturbed lipid metabolism plays a role in cancer risk and development, pointing towards parallels in metabolic derangements between metabolic diseases and cancer. An important feature of disturbed lipid metabolism is the increase in circulating low-density lipoproteins, which can be oxidized (oxLDL). Elevated oxLDL and the level of its receptors have been positively associated with increased risk of various types of cancer. This review discusses the pro-oncogenic role of oxLDL in tumor development, progression and potential therapies, and provides insights into the underlying mechanisms.
Topics: Animals; Carcinogenesis; Disease Progression; Humans; Lipoproteins, LDL; Neoplasms
PubMed: 31479734
DOI: 10.1016/j.bbalip.2019.158518 -
Journal of Biomedical Materials... Aug 2022Lowering of low-density lipoprotein (LDL) levels in blood of patients with hyperlipidaemia can effectively prevent the progression of atherosclerosis and coronary heart...
Lowering of low-density lipoprotein (LDL) levels in blood of patients with hyperlipidaemia can effectively prevent the progression of atherosclerosis and coronary heart disease. The present study demonstrated a facile synthesis strategy to prepare biomembrane-mimetic LDL adsorbent (PVA@COOH-PE) via directional immobilization of phospholipid onto macro-porous cross-linked poly(vinyl alcohol) spheres. The binding between the prepared adsorbent and LDL particles simulates the cytosolic lipid droplets to form a lipid-packing structure. The adsorbent possesses satisfactory removal efficiency for LDL and total cholesterol (TCH) in hyperlipemia serum, while remains high-density lipoprotein (HDL) concentration within the normal range. The adsorption capacities for LDL and TCH are about 1.13 and 1.74 mg/ml respectively, which are nearly three and four times higher than that of HDL (0.42 mg/ml). The adsorbent also possesses satisfactory anticoagulant properties, causes negligible effect on blood cells and produces low hemolysis ratios. The excellent blood compatibility plus LDL removal efficiency of PVA@COOH-PE indicates its good application prospect as hemoperfusion adsorbent in the treatment of hyperlipidaemia.
Topics: Adsorption; Hemoperfusion; Humans; Hyperlipidemias; Lipoproteins, LDL; Polyvinyl Alcohol
PubMed: 35294093
DOI: 10.1002/jbm.b.35053 -
Journal of the American Heart... Aug 2020Background Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of...
Background Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage-derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production. Methods and Results We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low-density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration-dependent manner (293% increase; <0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (<0.05), and oxLDL-induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL-induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (<0.01) and caspase 3/7 activation increased MΦMP production by 208% (<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL-induced caspase 3/7 activation and attenuated oxLDL-stimulated MΦMP production and tissue factor content by 60% (<0.01) and 43% (<0.05), respectively. Conclusions OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering.
Topics: Cell-Derived Microparticles; Flow Cytometry; Humans; Lipoproteins, LDL; Macrophages; Thrombin; Thromboplastin; Thrombosis
PubMed: 32750308
DOI: 10.1161/JAHA.120.015878 -
Cells Jan 2023Alterations in lipid composition and disturbed lipoprotein metabolism are involved in the pathomechanism of Huntington's disease (HD). Here, we measured 112 lipoprotein...
Alterations in lipid composition and disturbed lipoprotein metabolism are involved in the pathomechanism of Huntington's disease (HD). Here, we measured 112 lipoprotein subfractions and components in the plasma of 20 normal controls, 24 symptomatic (sympHD) and 9 presymptomatic (preHD) HD patients. Significant changes were found in 30 lipoprotein subfractions and components in all HD patients. Plasma levels of total cholesterol (CH), apolipoprotein (Apo)B, ApoB-particle number (PN), and components of low-density lipoprotein (LDL) were lower in preHD and sympHD patients. Components of LDL4, LDL5, LDL6 and high-density lipoprotein (HDL)4 demonstrated lower levels in preHD and sympHD patients compared with controls. Components in LDL3 displayed lower levels in sympHD compared with the controls, whereas components in very low-density lipoprotein (VLDL)5 were higher in sympHD patients compared to the controls. The levels of components in HDL4 and VLDL5 demonstrated correlation with the scores of motor assessment, independence scale or functional capacity of Unified Huntington's Disease Rating Scale. These findings indicate the potential of components of VLDL5, LDL3, LDL4, LDL5 and HDL4 to serve as the biomarkers for HD diagnosis and disease progression, and demonstrate substantial evidence of the involvement of lipids and apolipoproteins in HD pathogenesis.
Topics: Humans; Triglycerides; Huntington Disease; Lipoproteins; Lipoproteins, LDL; Apolipoproteins B; Biomarkers
PubMed: 36766727
DOI: 10.3390/cells12030385 -
Circulation Dec 2019
Topics: Antibodies, Monoclonal, Humanized; Cholesterol; Humans; Intracranial Hemorrhages; Lipoproteins, LDL; Stroke
PubMed: 31707828
DOI: 10.1161/CIRCULATIONAHA.119.044275 -
Cellular and Molecular Biology... Jan 2021Atherosclerosis (AS) is a widespread pathological coronary heart disease (CHD), which, along with other cardiovascular diseases (CVDs), is the primary cause of global... (Review)
Review
Atherosclerosis (AS) is a widespread pathological coronary heart disease (CHD), which, along with other cardiovascular diseases (CVDs), is the primary cause of global mortality. It is initiated by the accumulation of cholesterol-laden macrophages in the artery wall, thereby forming the foam-cells, the hallmark of AS. Increased influx of oxidized LDL and decreased efflux of free cholesterol from macrophages constitute major factors that mediate the progression of AS. Natural compounds treatment and prevention of AS being an effective approach for a long time. Currently, as interests in medicinally important natural products increased that including medicinal herbs, numerous studies on natural compounds effective forAS have been reported. In the current review, we shed light on the available plant-based natural compounds as AS modulators with underlying mechanisms that may lead to potential therapeutic implications.
Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol; Foam Cells; Humans; Lipoproteins, LDL; Molecular Structure; Phytochemicals; Phytotherapy; Plant Extracts; Plants, Medicinal
PubMed: 34817349
DOI: 10.14715/cmb/2021.67.1.27 -
Circulation Journal : Official Journal... Oct 2021
Prospects for the Combined Evaluation of Circulating Malondialdehyde-Modified Low-Density Lipoprotein Measurement and High-Intensity Plaque on T1-Weighted Cardiac Magnetic Resonance Angiography in the Prediction of Cardiovascular Events.
Topics: Coronary Artery Disease; Humans; Lipoproteins, LDL; Magnetic Resonance Angiography; Malondialdehyde; Plaque, Atherosclerotic
PubMed: 34483229
DOI: 10.1253/circj.CJ-21-0666 -
Molecules and Cells Nov 2019The incidence of atherosclerosis is higher among patients with several autoimmune diseases such as psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematosus... (Review)
Review
The incidence of atherosclerosis is higher among patients with several autoimmune diseases such as psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It is well documented that innate immune cells including macrophages and dendritic cells sense lipid species such as saturated fatty acids and oxidized low-density lipoprotein and produce pro-inflammatory cytokines and chemokines. However, whether a hyperlipidemic environment also impacts autoimmune T cell responses has been unclear. Among CD4+ T cells, Th17 and follicular helper T (Tfh) cells are known to play pathogenic roles in the development of hyperlipidemiaassociated autoimmune diseases. This review gives an overview of the cellular and molecular mechanisms by which dysregulated lipid metabolism impacts the pathogenesis of autoimmune diseases, with specific emphasis on Th17 and Tfh cells.
Topics: Autoimmune Diseases; Autoimmunity; Cytokines; Dendritic Cells; Fatty Acids; Humans; Lipid Metabolism; Lipoproteins, LDL; Macrophages; T-Lymphocytes, Helper-Inducer
PubMed: 31766832
DOI: 10.14348/molcells.2019.0196