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ABSTRACT: We sought to study whether patients with familial combined hyperlipidemia (FCH) or carotid atherosclerosis have modified circulating solubilized Fas ligand (sFasL) levels, as well as the potential modifications by atorvastatin. We also examined the effect of atorvastatin on FasL expression and sFasL release in cytokine-stimulated cultured human endothelial cells (ECs).
In normal situations, FasL is expressed in most cells, including ECs. Proinflammatory stimuli can downregulate its expression in ECs and facilitate the vascular infiltration of inflammatory cells.
We have measured sFasL plasma levels (by ELISA) in 58 patients with FCH, 14 normocholesterolemic patients with carotid atherosclerosis, and 15 healthy volunteers. We analyzed FasL expression (by Western blot analysis) and sFasL release in cultured ECs stimulated with tumor necrosis factor (TNF)-alpha.
Solubilized FasL levels were decreased in hyperlipidemic patients (49 pg/ml), as compared with healthy volunteers (123 pg/ml, p < 0.0001). Patients were randomized to atorvastatin (n = 28) or bezafibrate (n = 30) during 12 months. Atorvastatin treatment increased sFasL concentrations (111 pg/ml, p < 0.0001), reaching normal values. However, treatment with bezafibrate only marginally affected sFasL (85 pg/ml, p < 0.05). Solubilized FasL was also diminished in patients with carotid atherosclerosis (39 pg/ml), and intensive treatment with atorvastatin normalized sFasL levels (90 pg/ml, p = 0.02). Finally, atorvastatin prevented the diminution of FasL expression and sFasL release elicited by TNF-alpha in cultured ECs.
Patients with FCH or carotid atherosclerosis have decreased circulating sFasL levels, probably indicating endothelial dysfunction, but treatment with atorvastatin restored normal blood levels. These data provide a novel effect of atorvastatin and add support for the well-known anti-inflammatory properties of statins.
Journal of the American College of Cardiology 04/2004; 43(7):1188-94. · 14.16 Impact Factor
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ABSTRACT: In the present study, we compared the effect of atorvastatin (1 mg.kg(-1).day(-1)) and quinapril (0.5 mg.kg(-1).day(-1)) alone or in combination on inflammatory markers, endothelial function, intimal thickening and fibrinolytic balance in rabbits fed with either a control diet or a diet containing 1% (v/v) cholesterol for 12 weeks. Atorvastatin alone or in combination partially prevented the increase in cholesterol plasma levels observed in rabbits fed with the cholesterol-rich diet, but did not modify blood pressure levels. Quinapril administration did not alter any of these parameters in any group. Hypercholesterolaemia increased plasma levels of interleukin-1beta, interleukin-6, interferon-gamma and C-reactive protein, reduced acetylcholine-induced relaxation and produced intimal thickening. Likewise, atherosclerotic rabbits had reduced plasma tissue-type plasminogen activator activity and D-dimer levels and an increase in plasminogen-activator inhibitor-1 activity. Both drugs enhanced acetylcholine-induced relaxation, reduced intimal thickening and improved fibrinolytic balance in atherosclerotic rabbits in a similar manner. Their combination did not induce additive effects on these parameters. However, only the combination of both drugs was able to prevent the increase in inflammatory markers induced by hypercholesterolaemia. In summary, these data suggest that quinapril and atorvastatin had comparable beneficial effects on the alterations of vascular function and structure as well as fibrinolytic balance in atherosclerotic rabbits. In addition, the combination of atorvastatin and quinapril exerts a synergistic effect on inflammatory markers, which individual treatment, at the doses used, was not able to modify.
Clinical Science 01/2004; 105(6):655-62. · 4.61 Impact Factor
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ABSTRACT: HMG-CoA reductase inhibitors reduce cardiovascular mortality, although the mechanisms of action have not been completely elucidated. The presence of T cells and apoptotic cells in atherosclerotic plaques is well established, the reduction of cellular content being a marker of their vulnerability. One of the main mechanisms of cell death activation is the Fas-Fas ligand (FasL) system.
We studied whether HMG-CoA reductase inhibitors can regulate FasL expression and cytotoxicity in human T cells (Jurkat cells). Activation of Jurkat cells with phorbol esters and ionomycin increased FasL expression, an effect prevented by atorvastatin or simvastatin. Mevalonate and geranylgeranylpyrophosphate but not farnesylpyrophosphate prevented the effect of atorvastatin, indicating that protein geranylation was involved in FasL expression. The C3 exotoxin, which selectively inactivates Rho proteins, also decreased FasL expression on T cells. Overexpression of constitutively active RhoA increased FasL expression in Jurkat cells, and dominant-negative RhoA decreased FasL expression in activated cells, indicating that RhoA is implicated in FasL expression. Atorvastatin also decreased cytotoxic activity of activated Jurkat cells on FasL-sensitive cells. Finally, atorvastatin treatment reduced FasL expression in peripheral blood mononuclear cells and human carotid atherosclerotic plaques.
Atorvastatin regulates FasL expression in T cells, probably because of the inhibition of RhoA prenylation. These results provide novel information by which atorvastatin may regulate the cytotoxic activity of T cells and the number of cells in the atherosclerotic plaque.
Circulation 10/2003; 108(12):1506-13. · 14.74 Impact Factor
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José L Pérez-Castrillón,
Jesús Silva,
Isabel Justo,
Alberto Sanz,
Miguel Martín-Luquero,
Rosa Igea,
Pilar Escudero,
Carol Pueyo, Cristina Díaz,
Gonzalo Hernández,
Antonio Dueñas
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ABSTRACT: Many alterations in extracellular metabolism of calcium have been associated to hypertension, but the number of studies relating this disease with osteoporosis is extremely low. This study clarifies the therapeutic effect of three treatments-quinapril, quinapril + hydrochlorothiazide (HCTZ), enalapril-on bone remodeling markers, bone mineral density (BMD) in hypertensive patients, and relationship with angiotensin converting enzyme (ACE) polymorphism.
This open, prospective study included 134 patients with low-to-moderate hypertension and stable BMD according to Joint National Committee criteria and 96 patients completed the study. After a washout period, patients were randomized to one of the three treatments, which they received for 1 year. Analyses of blood and urine samples and densitometric studies on lumbar spine were performed.
Calcium and 25-hydroxyvitamin D levels increased (9.5 +/-0.3 and 9.6 +/-0.3 mg/dL, P =.01 and 46 +/-22 and 58 +/-22 nmol/L, P =.026, respectively) in the quinapril-treated group and calcium levels increased (9.4 +/-0.6 and 9.8 +/-0.4 mg/dL, P =.001) in the quinapril-HCTZ-treated group. The 1, 25-dihydroxyvitamin D levels, calciuria, and calcium/creatinine ratio decreased (64 +/-23 and 43 +/-16 nmol/L, P =.0001;209 +/-93 and 161 +/-93 mg/24 h, P =.0022;0.21 +/-0.09 and 0.17 +/-0.11, P =.04, respectively). In the enalapril-treated group 1, 25-dihydroxyvitamin D levels (61 +/-27 and 42 +/-19 nmol/L, P =.0022) decreased. Only women presented a statistical significance (1.064 +/-0.16 g/cm(2), P =.034) between ID+II polymorphism and BMD decrease, and between DD polymorphism with less BMD under baseline conditions and a BMD increase (1.070 +/-0.16 g/cm(2), P =.017) after ACE inhibitor treatment.
The ACE inhibitors have a beneficial effect on BMD and calcium metabolism alterations in hypertensive subjects. Concerning BMD response, women presenting with the II+ID polymorphism had a poor response to antihypertensive drug treatment, whereas women with the DD polymorphism responded better. This is the first study demonstrating a relationship between ACE polymorphism and BMD response and antihypertensive ACE inhibitor treatment.
American Journal of Hypertension 07/2003; 16(6):453-9. · 3.18 Impact Factor
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Emilio Ros,
Josefina Oliván,
José M Mostaza,
Miquel Vilardell,
Xavier Pintó,
Fernando Civeira,
A Hernández,
Pedro Marqués da Silva,
A Rodriguez-Botaro,
Daniel Zambón,
Joan Lima,
José A Gómez-Gerique, Cristina Díaz,
Rosa Arístegui,
José M Sol,
Gonzalo Hernández
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ABSTRACT: Objective: Combined hyperlipidaemia is a common and highly atherogenic lipid phenotype with multiple lipoprotein abnormalities that are difficult to normalise with single-drug therapy. The ATOMIX multicentre, controlled clinical trial compared the efficacy and safety of atorvastatin and bezafibrate in patients with diet-resistant combined hyperlipidaemia. Patients and study design: Following a 6-week placebo run-in period, 138 patients received atorvastatin 10mg or bezafibrate 400mg once daily in a randomised, double-blind, placebo-controlled trial. To meet predefined low-density lipoprotein-cholesterol (LDL-C) target levels, atorvastatin dosages were increased to 20mg or 40mg once daily after 8 and 16 weeks, respectively. Results: After 52 weeks, atorvastatin achieved greater reductions in LDL-C than bezafibrate (percentage decrease 35 vs 5; p < 0.0001), while bezafibrate achieved greater reductions in triglyceride than atorvastatin (percentage decrease 33 vs 21; p < 0.05) and greater increases in high-density lipoprotein-cholesterol (HDL-C) [percentage increase 28 vs 17; p < 0.01 ]. Target LDL-C levels (according to global risk) were attained in 62% of atorvastatin recipients and 6% of bezafibrate recipients, and triglyceride levels <200 mg/dL were achieved in 52% and 60% of patients, respectively. In patients with normal baseline HDL-C, bezafibrate was superior to atorvastatin for raising HDL-C, while in those with baseline HDL-C <35 mg/dL, the two drugs raised HDL-C to a similar extent after adjustment for baseline values. Both drugs were well tolerated. Conclusion: The results show that atorvastatin has an overall better efficacy than bezafibrate in concomitantly reaching LDL-C and triglyceride target levels in combined hyperlipidaemia, thus supporting its use as monotherapy in patients with this lipid phenotype.
Clinical Drug Investigation 01/2003; 23(3):153-65. · 1.82 Impact Factor
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ABSTRACT: Evidence suggests that the inhibition of both acyl-CoA:cholesterol acyltransferase and hydroxymethyl glutaryl-CoA reductase causes a synergistic direct antiatherosclerotic effect on the vessel wall. To investigate this synergism in a single cell type and to avoid the confounding effect of plasma cholesterol lowering by these drugs, we have used an in vitro model of human macrophages (phorbol ester-treated THP-1 cells). In macrophages incubated simultaneously with acetyl low-density lipoproteins, the novel acyl-CoA:cholesterol acyltransferase inhibitor avasimibe (0.01-0.5 microM) caused a concentration-dependent reduction in cell cholesteryl ester content that was not accompanied by an increase in intracellular free cholesterol. A 5 microM concentration of atorvastatin enhanced by approximately twofold the ability of 0.5 microM avasimibe to reduce the mass of esterified cholesterol, and this was reversed by co-incubation with 200 microM mevalonate or 10 microM geranyl-geraniol. Based on these data, we propose that the synergism between acyl-CoA:cholesterol acyltransferase and hydroxymethyl glutaryl-CoA reductase inhibitors found in several in vivo studies may be explained by a direct additive effect of both agents reducing the lipid content of the macrophages present in the lesion area.
European Journal of Pharmacology 10/2002; 451(1):11-7. · 2.52 Impact Factor
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ABSTRACT: We aimed to investigate the effect of atorvastatin (5 and 30 mg/kg/day for 2 weeks) on hepatic lipid metabolism in a well established model of dietary hypertriglyceridemia, the fructose-fed rat. Fructose feeding (10% fructose in drinking water for 2 weeks) induced hepatic lipogenesis and reduced peroxisome proliferator-activated receptor alpha (PPARalpha) expression and fatty acid oxidation. As a result, plasma and liver triglyceride and plasma apolipoprotein B (apoB) levels were increased. Atorvastatin, 5 and 30 mg/kg during 2 weeks, markedly reduced plasma triglyceride, but decreased apoB levels only at the highest dose tested (50%). Triglyceride biosynthetic enzymes and microsomal triglyceride transfer protein were unchanged, whereas liver PPARalpha, acyl-CoA oxidase, and carnitine palmitoyltransferase I mRNA levels (1.9-, 1.25-, and 3.4-fold, respectively) and hepatic fatty acid beta-oxidation activity (1.25-fold) were increased by atorvastatin at 30 mg/kg. Furthermore, hepatic triglyceride content (45%) and plasma nonesterified fatty acids (NEFAs) (49%) were reduced. These results show for the first time that liver triglyceride increase in fructose-fed rats is linked to decreased expression of PPARalpha, which is prevented by atorvastatin treatment. The increase in PPARalpha expression caused by atorvastatin was associated with reduced liver triglyceride and plasma NEFA levels.
Journal of Pharmacology and Experimental Therapeutics 08/2002; 302(1):232-9. · 3.83 Impact Factor
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ABSTRACT: Treatments with high doses of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors may induce the expression of sterol regulatory element binding protein (SREBP)-target genes, causing different effects from those attributed to the reduction of hepatic cholesterol content. The aim of this study was to investigate the effects of high doses of statins on the key enzymes involved in VLDL production in normolipidemic rats. To examine whether the effects caused by statin treatment are a consequence of HMG-CoA reductase inhibition, we tested the effect of atorvastatin on these enzymes in mevalonate-fed rats. Atorvastatin and simvastatin enhanced not only HMG-CoA reductase but also the expression of the SREBP-2 gene itself. As a result of the overexpression of SREBP-2 caused by the statin treatment, genes regulated basically by SREBP-1, as FA synthase and acetyl-coenzyme A carboxylase, were also induced and their mRNA levels increased. DAG acyltransferase and microsomal TG transfer protein mRNA levels as well as phosphatidate phosphohydrolase activity were increased by both statins. Simvastatin raised liver cholesterol content, ACAT mRNA levels, and CTP:phosphocholine cytidylyltransferase activity, whereas it reduced liver DAG and phospholipid content. Mevalonate feeding reversed all changes induced by the atorvastatin treatment. These results show that treatment with high doses of statins induces key enzymes controlling rat liver lipid synthesis and VLDL assembly, probably as a result of SREBP-2 overexpression. Despite the induction of the key enzymes involved in VLDL production, both statins markedly reduced plasma TG levels, suggesting that different mechanisms may be involved in the hypotriglyceridemic effect of statins at high or low doses.
Lipids 06/2002; 37(5):445-54. · 2.13 Impact Factor
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Juan A Gómez-Gerique,
Emilio Ros,
Josefina Oliván,
Jose M Mostaza,
Miquel Vilardell,
Xavier Pintó,
Fernando Civeira,
Antonio Hernández,
Pedro Marqués da Silva,
Antonio Rodriguez-Botaro,
Daniel Zambón,
Joan Lima, Cristina Díaz,
Rosa Aristegui,
Josep M Sol,
José Chaves,
Gonzalo Hernández
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ABSTRACT: C-reactive protein (CRP) is a non-specific but sensitive marker of underlying systemic inflammation. High CRP plasma levels correlate with risk for future cardiovascular events. The present study evaluated the effects of atorvastatin (10-40 mg) and bezafibrate (400 mg) on CRP concentrations after 6 and 12 months of treatment in 103 patients with combined (mixed) hyperlipidemia. The number of cardiovascular risk factors present in a given patient was associated with baseline CRP levels. After 6 months and 1 year, atorvastatin treatment was associated with significant (P<0.001) decreases from baseline of CRP concentrations by 29 and 43%, respectively, while bezafibrate-treated patients showed non-significant reductions of 2.3 and 14.6%, respectively (P=0.056 and 0.005 for the respective differences between the two treatment arms at 6 months and 1 year). The magnitude of change in CRP after 1 year was directly related to baseline CRP levels. Covariance analysis showed that CRP decreases in the atorvastatin group were unrelated to total cholesterol and LDL cholesterol reductions; however, they were directly related to triglyceride changes (r=0.28, P=0.047) and inversely related to HDL cholesterol changes (r=-0.28, P=0.045). A model including baseline CRP values and treatment effect showed that atorvastatin use was a significant predictor of change in CRP levels over time (beta=0.82, P=0.023). These results suggest a potential anti-atherosclerotic additional benefit of atorvastatin in patients at a risk of cardiovascular disease.
Atherosclerosis 06/2002; 162(2):245-51. · 3.79 Impact Factor
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Miguel Angel Hernández-Presa,
José Luis Martín-Ventura,
Mónica Ortego,
Almudena Gómez-Hernández,
José Tuñón,
Purificación Hernández-Vargas,
Luis Miguel Blanco-Colio,
Sebastián Mas,
César Aparicio,
Luis Ortega,
Fernando Vivanco,
Juan Gómez Gerique, Cristina Díaz,
Gonzalo Hernández,
J Egido
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ABSTRACT: Inflammation is involved in the genesis and rupture of atherosclerotic plaques. We assessed the effect of atorvastatin (ATV) on the expression of cyclooxygenase-2 (COX-2) and other proinflammatory molecules in a rabbit model of atherosclerosis. Fourteen animals underwent injury of femoral arteries and 2 weeks of atherogenic diet. Afterwards, they were randomized to receive either 5 mg/kg per day of ATV (n=8) or no treatment (NT, n=6) during 4 weeks, and were finally killed. ATV reduced lipid levels, neointimal size (0.13 (0.03-0.29) mm(2) vs 0.65 (0.14-1.81) mm(2), P=0.005) and the percentage of neointimal area positive for macrophages (1% (0-3) vs 19% (5-32), P=0.001), COX-2 (32% (23-39) vs 60% (37-81) P=0.019), interleukin-8 (IL-8) (23% (3-63) vs 63% (25-88) P=0.015), and metalloproteinase-3 (19% (12-34) vs 42% (27-93), P=0.010), without significant differences in COX-1 expression (immunohistochemistry). In situ hybridization confirmed a decreased expression of COX-2 mRNA (22% (5-40) vs 43% (34-59) P=0.038). The activity of nuclear factor-kappaB, which controls many proinflammatory genes including COX-2, was reduced in atherosclerotic lesions (3538 (2663-5094) vs 8696 (5429-11312)) positive nuclei per mm(2), P=0.001) and circulating mononuclear cells (2966 vs 17130 arbitrary units). In cultured vascular smooth muscle cells, ATV reduced the expression of COX-2 mRNA induced by IL-1beta and TNF-alpha without affecting COX-1 expression. In conclusion, ATV, besides decreasing a number of inflammatory mediators in the atherosclerotic lesion, significantly downregulates COX-2 both in vivo and in vitro. These anti-inflammatory actions could partially account for the reduction of acute coronary events achieved by statins.
Atherosclerosis 02/2002; 160(1):49-58. · 3.79 Impact Factor
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ABSTRACT: The effects of atorvastatin (3 mg kg−1) and simvastatin (3 mg kg−1) on hepatic enzyme activities involved in very low density lipoprotein metabolism were studied in coconut oil/cholesterol fed rabbits.Plasma cholesterol and triglyceride levels increased 19 and 4 fold, respectively, after 7 weeks of feeding.Treatment with statins during the last 4 weeks of feeding abolished the progression of hypercholesterolaemia and reduced plasma triglyceride levels.3-Hydroxy-3-methyl-glutaryl Coenzyme A reductase, acyl-coenzyme A:cholesterol acyltransferase, phosphatidate phosphohydrolase and diacylglycerol acyltransferase activities were not affected by drug treatment. Accordingly, hepatic free cholesterol, cholesteryl ester and triglyceride content were not modified.Simvastatin treatment caused an increase (72%) in lipoprotein lipase activity without affecting hepatic lipase activity.Atorvastatin caused a reduction in hepatic phospholipid content and a compensatory increase in CTP:phosphocholine cytidylyl transferase activity.The results presented in this study suggest that, besides the inhibitory effect on 3-hydroxy-3-methyl-glutaryl Coenzyme A reductase, simvastatin and atorvastatin may have additional effects that contribute to their triglyceride-lowering ability.British Journal of Pharmacology (1999) 127, 1479–1485; doi:10.1038/sj.bjp.0702668
British Journal of Pharmacology 06/1999; 127(6):1479 - 1485. · 4.41 Impact Factor
