Browsing by Author "Hernández, Gonzalo"
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Item 3-Hydroxy-3-methylglutaryl coenzyme a reductase inhibitors decrease Fas ligand expression and cytotoxicity in activated human T lymphocytes(2003-09-23) Blanco-Colio, Luis Miguel; Muñoz-García, Begoña; Martín-Ventura, Jose Luis; Lorz, Corina; Díaz, Cristina; Hernández, Gonzalo; Egido, Jesús; Centros PRE-FUSION TECNALIA - (FORMER)Background-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. Methods and Results-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. Conclusions-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.Item Randomized crossover study of gemfibrozil versus lovastatin in familial combined hyperlipidemia: Additive effects of combination treatment on lipid regulation(1999) Zambón, Daniel; Ros, Emilio; Rodriguez-Villar, Camino; Laguna, Juan Carlos; Vázquez, Manuel; Sanllehy, Carolina; Casais, Elena; Sol, Josep M.; Hernández, Gonzalo; Centros PRE-FUSION TECNALIA - (FORMER)The most appropriate therapy for combined hyperlipidemia remains to be determined. We compared the lipid-regulating effects of gemfibrozil and lovastatin in 30 patients with familial combined hyperlipidemia (FCHL) in a randomized, double-blind, placebo-controlled crossover study including 8- week courses of one drug followed by a washout period and a crossover phase to the alternate drug. After completion of the trial, open-label combination therapy was given for up to 12 months. Lovastatin was more efficacious than gemfibrozil in the reduction of total cholesterol (23% v 9%, P < .001) and low-density lipoprotein (LDL) cholesterol (28% v 2%, P < .001), whereas gemfibrozil surpassed lovastatin in the reduction of triglycerides (48% v 0%, P < .001) and very-low-density lipoprotein (VLDL) cholesterol (50% v 19%, P = .005) and the increase of high-density lipoprotein (HDL) cholesterol (18% v 4%, P = .005), Lovastatin caused a greater decline in total apolipoprotein B (apo B) and LDL apo B than gemfibrozil, whereas VLDL apo B decreased only after gemfibrozil therapy. Drug-induced changes in lipoprotein composition indicated that gemfibrozil reduced both the number and size of VLDL particles and lovastatin decreased the number of LDL particles. Combined treatment was safe and had additive effects on lipids, causing significant (P < .001) reductions in total cholesterol (32%), triglycerides (51%), LDL cholesterol (34%), and apo B (26%) and an increase in HDL cholesterol (19%). Target LDL cholesterol levels were achieved only in 11% of patients given gemfibrozil alone and triglycerides decreased to target levels in 22% after lovastatin alone, whereas combined therapy normalized both lipid fractions in 96% of patients. Thus, in FCHL gemfibrozil has no effect on LDL cholesterol levels but favorably influences the putative atherogenic alterations of lipoprotein composition that are related to hypertriglyceridemia. Conversely, lovastatin markedly decreases LDL cholesterol but has little effect on triglyceride- rich lipoproteins. Combination treatment safely corrects all of the lipid abnormalities in most patients.