Different Effect of Statins on Platelet Oxidized-LDLReceptor (CD36 and LOX-1) Expressionin Hypercholesterolemic Subjects (original) (raw)
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Atorvastatin reduces platelet-oxidized-LDL receptor expression in hypercholesterolaemic patients
European Journal of Clinical Investigation, 2005
Background Oxidized-LDL (ox-LDL) are proatherogenic and platelet-activating molecules. Atorvastatin reduces platelet activity before cholesterol-lowering action. CD36 and lectin-like oxidized-LDL receptor-1 (LOX-1) are specific ox-LDL receptors expressed also in platelets. This study was planned to address whether the possible rapid effect of atorvastatin on platelets could be related to modulation of ox-LDL receptors. Materials and methods Forty-eight hypercholesterolaemic subjects requiring statin treatment (atorvastatin 20 mg day − 1) after an ineffective diet regimen were evaluated for complete lipid-profile (chromogenic); P-selectin (P-sel), CD36 and LOX-1 expression (cytofluorimetric detection); circulating and platelet-associated ox-LDL (ox-and Pox-LDL, ELISA); and intracellular citrullin recovery (iCit, HPLC) at baseline and 3, 6 and 9 days after inclusion in the study. Moreover, we studied 48 normal controls matched for sex and age. Results Platelet activity expressed by P-sel (in resting and thrombin-activated cells), CD36 and LOX-1 were increased in hypercholesterolaemic subjects (all P < 0•01). Atorvastatin induced a reduction of CD36 at 6 days (P < 0•05); and P-sel in resting (P < 0•001) and activated cells (P < 0•001) and LOX-1 were reduced at 9 days (all P < 0•001) in association with decreased Pox-LDL (P < 0•001) and increased iCit (P < 0•01). All data were obtained before a significant reduction of LDL and ox-LDL was achieved (P = 0•109 and 0•113). Discussion Present data suggest that platelet deactivation by atorvastatin is related to CD36 and LOX-1 expression reduction before significant LDL changes. Moreover, the modulation of LOX-1 can be considered a self-relevant antiatherothrombotic action of atoravastin owing to the important role of this receptor in the ox-LDL-mediated vascular damage.
Atherosclerosis, 2011
Objectives: We examined the time-dependent effects of atorvastatin and rosuvastatin on in vivo oxidative stress and platelet activation, to assess whether these phenomena are related to any pleiotropic effect of any statin or to their LDL-lowering effect. We also asked whether the presence of specific allele frequencies in carriers of the 3 UTR/lectin-like oxidized LDL receptor-1 (LOX-1) polymorphism may influence the effect of either statin. Methods: We included 60 hypercholesterolemic subjects, previously screened for LOX-1 3 UTR polymorphism, randomized, according to genetic profile (15 T and 15 C carriers for each arm), to atorvastatin 20 mg/day or rosuvastatin 10 mg/day. Results: After 8 weeks, atorvastatin and rosuvastatin were associated with comparable, significant reductions in LDL cholesterol (40.8% and 43.6%, respectively), plasma hs-CRP (9.5% vs. 13.8%), urinary 11-dehydro-thromboxane (TX) B 2 (38.9% vs. 27.1%) and 8-iso-prostaglandin (PG) F 2␣ (39.4% vs. 19.4%). The impact of rosuvastatin or atorvastatin on CRP, 8-iso-PGF 2␣ , and 11-dehydro-TXB 2 did not differ according to the LOX-1 haplotype. On multiple regression analyses, only CRP and LDL were independent predictors of 11-dehydro-TXB 2 , and only LDL was a significant predictor of 8-iso-PGF 2␣. Conclusions: Both atorvastatin and rosuvastatin cause comparable reductions of thromboxane-dependent platelet activation, lipid peroxidation and inflammation. The presence of 3 UTR/LOX-1 polymorphism does not affect the changes induced by either statin.
Effect of statins on platelet function in patients with hyperlipidemia
Archives of Medical Science, 2013
A b s t r a c t I In nt tr ro od du uc ct ti io on n: : It is generally assumed that cholesterol reduction by statins is the predominant therapeutic result underlying their beneficial effects in cardiovascular disease. However, the action of statins may be partially independent of their effects on plasma cholesterol levels, as they combine lipid lowering with positive effects on hemorheological conditions and endothelial function. We evaluated the impact of statin treatment on platelet adhesion to fibrinogen (spontaneous and ADP-activated), along with ADP, collagen or ristocetin-induced aggregation in type II hyperlipidemic patients. M Ma at te er ri ia al l a an nd d m me et th ho od ds s: : The study group included 70 persons: 50 patients affected by type II hyperlipidemia without concomitant diseases and 20 healthy volunteers. The effects of 8-week statin treatment (atorvastatin 10 mg/day, simvastatin 20 mg/day, or pravastatin 20 mg/day) on platelet activation were evaluated. R Re es su ul lt ts s: : Regardless of the type of statin, a significant decrease in ADP-induced platelet aggregation was observed: for atorvastatin 50.6 ±12.8% vs. 41.1 ±15.8% (p < 0.05), for simvastatin 57.2 ±18.0% vs. 44.7 ±22.1% (p = 0.05), and for pravastatin 55.8 ±19.5% vs. 38.8 ±23.3% (p < 0.05). There was no significant effect of statins on collagen or ristocetin-induced platelet aggregation and adhesion. C Co on nc cl lu us si io on ns s: : Therapy with statins beneficially modifies ADP-induced platelet aggregation in patients with hyperlipidemia and does not affect spontaneous or ADP-induced platelet adhesion to fibrinogen and platelet aggregation induced by collagen or ristocetin.
International Journal of Cardiology, 2005
Background: The presence of increased levels of small dense (sd) LDL (phenotype B) is associated with a substantial increase of cardiovascular disease risk. Since lowering of plasma low-density lipoprotein-cholesterol (LDL-C) by statins involves an up-regulation of the LDL receptor, we questioned whether LDL lowering by atorvastatin affects different LDL subfractions equally. Methods: Fifty-four hypercholesterolemic patients, requiring treatment for prevention of coronary heart disease received atorvastatin (10, 20 or 40 mg/day), either as initial therapy (n=33), or as replacement therapy (n=21) for pravastatin or simvastatin (both at 40 mg/day). In addition to plasma lipid measurements, cholesterol LDL subfractions were separated and analysed before and after 3 months of treatment.
Journal of Thrombosis and Haemostasis, 2007
Summary. Objectives: We speculated that in patients with hypercholesterolemia CD40L overexpression could depend on low-density lipoprotein (LDL)-induced enhanced intraplatelet formation of O2·− and statin could reduce platelet CD40L via interference with platelet O2·− production. Background: CD40L is a protein with inflammatory and thrombotic properties. CD40L is upregulated in platelets from hypercholesterolemic (HC) patients but the underlying mechanism is unclear. Methods: Collagen-induced platelet CD40L and platelet O2·− expression were investigated in 40 HC patients and 40 healthy subjects. HC patients were then randomized to either a diet (n = 20) (group A) or atorvastatin 10 mg day (n = 20) (group B); the above variables were measured at baseline and after 3 and 30 days of treatment. O2·− and CD40L were also measured in vitro in LDL-treated platelets with or without nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor or atorvastatin added. Results: Compared with controls, HC patients showed higher values of platelet CD40L (P < 0.001) and O2·− (P < 0.001). Platelet CD40L was significantly correlated with O2·− (P < 0.001). The interventional trial showed no changes in group A and a significant and parallel decrease in platelet CD40L (P < 0.001) and O2·− (P < 0.001) in group B. In vitro studies demonstrated that LDL-induced platelet CD40L and GP IIb/IIIa (PAC1 binding) activation via the NADPH oxidase pathway. CD40L upregulation was counteracted by atorvastatin in a dose-dependent fashion. Conclusions: This study suggests that in patients with hypercholesterolemia platelet CD40L is upregulated via NADPH oxidase-dependent O2·− generation. Atorvastatin downregulated CD40L with an oxidative stress-mediated mechanism likely involving platelet NADPH oxidase, an effect that seemed to be independent of its cholesterol-lowering action.
Atherosclerosis, 2005
Oxidized-low density lipoproteins (ox-LDL) and the specific receptor LOX-1 are involved in atherogenesis and atherothrombosis. LOX-1 downregulation is associated with the anti-platelet action of atorvastatin. 3 UTR/T LOX-1 polymorphism has been associated with increased risk of coronary artery disease. This study was planned to determine whether LOX-1 genetic variations could affect anti-platelet action of atorvastatin. We studied by platelet P-selectin (P-sel), CD36 and LOX-1 expression (cytofluorimetric detection) whether differences in cellular activation could be suitable in 109 3 UTR/T carriers out of 201 hypercholesterolemic subjects treated with atorvastatin 20 mg/day. Hyperactivated platelets (P-sel in resting cells and % variation upon thrombin activation, p < 0.001) were detected at baseline in patients without significant differences between T or C carriers. P-sel and platelet-associated ox-LDL, were significantly decreased (all p < 0.001) in C carriers after one week of treatment before LDL reduction. In 3 UTR/T carriers P-sel was reduced (p < 0.01) after 6 weeks of treatment according to LDL and ox-LDL reduction. In 3 UTR/T carriers atorvastatin reduced platelet activity by LDL and ox-LDL lowering and not by rapid CD36 and LOX-1 downregulation as in C carriers. Such data suggest that in T carriers LDL lowering is needed to achieve anti-platelet action.
Effect of atorvastatin upon platelet activation in hypercholesterolemia, evaluated by flow cymetry
Thrombosis Research, 2005
Hyperlipidemia is a well established risk factor for cardiovascular disease and atherothrombotic events, in which platelet activation also plays a significant role. However, very few studies have addressed platelet activation in hypercholesterolemia, the potential effect of lipid lowering drugs upon platelet hyperfunction, and the question of whether changes in the latter are correlated to normalization of plasma lipids. This study used whole blood flow cytometry to assess in vivo and in vitro platelet activation in a group of 33 patients with hypercholesterolemia, and also the ex vivo effect of atorvastatin (20 mg/day) upon such activation. A control group of 40 normolipidemic volunteers matched in terms of age, sex and added risk factors to the patient group was used. The results showed that hypercholesterolemic patients had in vivo a significantly greater percentage of GPIIb/IIIa-and phosphatidylserine-positive platelets compared with the control group (4.62F3.51% and 2.58F1.19% versus 2.73F1.08% and 1.54F0.68%, respectively). In vitro response of CD62 expression to thrombin was also greater in the patients than in the controls (92.51F6.00% versus 89.63F10.72%, pb0.05). Atorvastatin therapy normalized platelet hyperfunction in the patients studied and reduced GPIIb/IIIa response to ADP (from 82.65F6.43% to 75.84F4.89%, pb0.01). A significant correlation can be seen between such normalization and the decrease in plasma levels of total and LDL cholesterol.
Atherosclerosis, 2017
Background and aims: High plasma LDL-cholesterol (LDL-C) and platelet responses have major pathogenic roles in atherothrombosis. Thus, statins and anti-platelet drugs constitute mainstays in cardiovascular prevention/treatment. However, the role of platelet tissue factor-dependent procoagulant activity (TF-PCA) has remained unexplored in hypercholesterolemia. We aimed to study platelet TF-PCA and its relationship with membrane cholesterol in vitro and in 45 hypercholesterolemic patients (HC-patients) (LDL-C >3.37 mmol/L, 130 mg/dL) and 37 control subjects (LDL-C <3.37 mmol/L). The effect of 1-month administration of 80 mg/day atorvastatin (n=21) and 20 mg/day rosuvastatin (n=24) was compared. Methods: Platelet TF-PCA was induced by GPIbα activation with VWF-ristocetin. Results: Cholesterol-enriched platelets in vitro had augmented aggregation/secretion and platelet FXa generation (1.65-fold increase, p=0.01). HC-patients had 1.5-, 2.3-and 2.5-fold increases in platelet cholesterol, TF protein and activity, respectively; their platelets had neither hyperaggregation nor endogenous thrombin generation (ETP). Rosuvastatin, but not atorvastatin, normalized platelet cholesterol, TF protein and FXa generation. It also increased slightly the plasma HDL-C levels, which correlated negatively with TF-PCA.
Circulation, 2005
Background-Soluble CD40L (sCD40L), a substance that maximally reflects in vivo platelet activation, is increased in patients with hypercholesterolemia. We investigated the relation between sCD40L and platelet CD4OL in hypercholesterolemic patients before and after a short-term treatment with atorvastatin. Methods and Results-Collagen-induced platelet CD40L and plasma levels of sCD40L and prothrombin fragment F1ϩ2, a marker of thrombin generation, were investigated in 30 hypercholesterolemic patients and 20 healthy subjects. Hypercholesterolemic patients were then randomized to either diet (nϭ15; group A) or atorvastatin 10 mg/d (group B); the aforementioned variables were measured at baseline and after 3 days of treatment. Compared with referents, hypercholesterolemic patients showed higher values of platelet CD40L (PϽ0.005), sCD40L (PϽ0.005), and F1ϩ2 (PϽ0.003). Platelet CD40L was significantly correlated with sCD40L (PϽ0.001), and the latter was significantly correlated with F1ϩ2 (PϽ0.001). The intervention trial showed no changes in group A but a significant decrease in platelet CD40L (PϽ0.01), sCD40L (PϽ0.002), and F1ϩ2 (PϽ0.03) in group B. In vitro studies demonstrated that cholesterol enhanced platelet CD40L and CD40L-mediated clotting activation by human monocytes; also, atorvastatin dose-dependently inhibited platelet CD40L expression and clotting activation by CD40L-stimulated monocytes. Conclusions-This study shows that, in hypercholesterolemia, platelet overexpression of CD40L may account for enhanced plasma levels of sCD40L and F1ϩ2. Atorvastatin exerts a direct antithrombotic effect via inhibition of platelet CD40L and CD40Lmediated thrombin generation, independently of its cholesterol-lowering effect. (Circulation. 2005;111:412-419.)
Effect of Statins on Platelet Activation and Function: From Molecular Pathways to Clinical Effects
BioMed Research International, 2021
Purpose. Statins are a class of drugs widely used in clinical practice for their lipid-lowering and pleiotropic effects. In recent years, a correlation between statins and platelet function has been unveiled in the literature that might introduce new therapeutic indications for this class of drugs. This review is aimed at summarizing the mechanisms underlying statin-platelet interaction in the cardiologic scenario and building the basis for future in-depth studies. Methods. We conducted a literature search through PubMed, Embase, EBSCO, Cochrane Database of Systematic Reviews, and Web of Science from their inception to June 2020. Results. Many pathways could explain the interaction between statins and platelets, but the specific effect depends on the specific compound. Some could be mediated by enzymes that allow the entry of drugs into the cell (OATP2B1) and others by enzymes that mediate their activation (PLA2, MAPK, TAX2, PPARs, AKT, and COX-1), recruitment and adhesion (LOX-1, C...