Efecto del ciprofibrato sobre el metabolismo del colesterol HDL y la capacidad antioxidante plasmática en el ratón / Effect of ciprofibrate on HDL cholesterol metabolism and plasma anti-oxidant capacity in mice

Antecedentes: Las dislipidemias, ya sea un aumento en los niveles de colesterol LDL y/o una disminución en las cifras de colesterol HDL, son muy relevantes para el desarrollo de la enfermedad cardiovascular ateroesclerótica, siendo el colesterol HDL bajo la dislipidemia más frecuente en la población chilena. Con respecto al colesterol HDL bajo y los tri -glicéridos elevados, los fibratos, agonistas del receptor nuclear PPAR-a que modula la transcripción de genes involucrados en el metabolismo de lípidos, representan una importante alternativa de manejo farmacológico de las dislipidemias. Sin embargo, estudios clínicos recientes no han sido concluyentes con respecto a su beneficio real sobre el control de la ateroesclerosis cuando se usan combinados con estatinas. Objetivo: Evaluar el impacto de la administración de fibratos sobre el metabolismo del colesterol HDL y la función antioxidante del plasma usando el ratón como modelo experimental. Metodología: Los ratones de la cepa C57BL/6 fueron tratados con ciprofibrato al 0,2% en dieta control durante 7 días. Luego del tratamiento, se analizaron los niveles de colesterol plasmático y triglicéridos, la expresión hepática de proteínas claves involucradas en el metabolismo de colesterol HDL, el contenido de colesterol hepático, la secreción de colesterol biliar y el daño oxidativo y la función antioxidante plasmática. Resultados: El tratamiento con ciprofibrato disminuyó significativamente los niveles de triglicéridos plasmáticos y la expresión hepática del receptor de HDL SR-BI, efecto que se correlacionó con un aumento en el tamaño de las partículas de HDL, pero no en los niveles de colesterol HDL. Además, el ciprofibrato disminuyó los niveles proteicos de los transportadores de colesterol ABCG1 y ABCG8, aunque no modificó ABCA1, en conjunto con una reducción del contenido hepático de colesterol y un aumento en la secreción de colesterol hacia la bilis. Finalmente, el uso de este hipolipemiante mejoró la función antioxidante del plasma, aunque se detectó un aumento en el daño nitrosativo de las proteínas plasmáticas. Conclusión: Este estudio ha permitido obtener nueva información sobre el efecto metabólico y funcional de la administración de fibratos en ratones, lo cual podría ayudar comprender los resultados de estudios clínicos recientes que han usado esta clase de hipolipemiantes en humanos.

Background: Increased serum levels of LDL cholesterol and/or decreased values of HDL cholesterol are very relevant for atherosclerotic cardiovascular disease. Low HDL cholesterol is the most prevalent dyslipidemia in the Chilean population. Regarding reduced HDL cholesterol and high triglyceride levels, fibrates, nuclear receptor PPAR-a agonists that modulate transcription of genes involved in lipid metabolism, represent an important alternative for pharmacological management of dyslipidemia. However, recent clinical studies have been inconclusive with respect to their real benefit on atherosclerosis when used in combination with statins. Aim: To evaluate the impact of fibrate administration on HDL cholesterol metabolism and antioxidant plasma functionality using the mouse as experimental model. Methodology: Using wild-type C57BL/6 mice, ciprofibrate was administered at 0.2% in chow diet for 7 days. After treatment, plasma cholesterol and triglycerides levels, hepatic expression of key proteins involved in HDL cholesterol metabolism, liver cholesterol content, biliary cholesterol secretion, and plasma oxidative damage and antioxidant function were analyzed. Results: Ciprofibrate treatment significantly decreased plasma triglycerides levels and hepatic HDL receptor SR-BI expression. This latter finding was associated with increased HDL particle size, without changes in HDL cholesterol levels. Furthermore, ci-profibrate decreased hepatic expression of cholesterol transporters ABCG1 and ABCG8, but not ABCA1, which correlated with reduced liver cholesterol content and increased biliary cholesterol secretion. Fina-lly, fibrate therapy improved plasma antioxidant func-tion, even though increased nitrosative plasma protein damage was detected. Conclusion: This study has provided new information on metabolic and functional effects derived from fibrate use in mice and it may help to better understand recent clinical findings using this lipid-lowering drug class in humans.

[Nicotinic acid increases cellular transport of high density lipoprotein cholesterol in patients with hypoalphalipoproteinemia]. / El ácido nicotínico aumenta el transporte celular de colesterol de las lipoproteínas de alta densidad en pacientes con hipoalfalipoproteinemia.

BACKGROUND: Plasma high density lipoproteins (HDL) are involved in reverse cholesterol transport mediated by the scavenger receptor class B type I (SR-BI). Nicotinic acid increases HDL cholesterol levels, even though its specific impact on SR-BI dependent-cellular cholesterol transport remains unknown. AIM: To determine the effect of nicotinic acid on HDL particle functionality in cholesterol efflux and uptake mediated by SR-BI in cultured cells in hypoalphalipoproteinemic patients. MATERIAL AND METHODS: In a pilot study, eight patients with low HDL (≤ 40 mg/dL) were treated with extended release nicotinic acid. HDL cholesterol and phospholipid levels, HDL2 and HDL3 fractions and HDL particle sizes were measured at baseline and post-therapy. Before and after nicotinic acid treatment, HDL particles were used for cholesterol transport studies in cells transfected with SR-BI. RESULTS: Nicotinic acid treatment raised total HDL cholesterol and phospholipids, HDL2 levels as well as HDL particle size. Nicotinic acid significantly increased HDL cholesterol efflux and uptake capacity mediated by SR-BI in cultured cells. CONCLUSIONS: Nicotinic acid therapy increases SR-BI-dependent HDL cholesterol transport in cultured cells, establishing a new cellular mechanism by which this lipid-lowering drug appears to modulate HDL metabolism in patients with hypoalphalipoproteinemia.

El ácido nicotínico aumenta el transporte celular de colesterol de las lipoproteínas de alta densidad en pacientes con hipoalfalipoproteinemia / Nicotinic acid increases cellular transport of high density lipoprotein cholesterol in patients with hypoalphalipoproteinemia

Background: Plasma high density lipoproteins (HDL) are involved in reverse cholesterol transport mediated by the scavenger receptor class B type I (SR-BI). Nicotinic acid increases HDL cholesterol levels, even though its specific impact on SR-BI dependent-cellular cholesterol transport remains unknown. Aim: To determine the effect of nicotinic acid on HDL particle functionality in cholesterol efflux and uptake mediated by SR-BI in cultured cells in hypoalphalipoproteinemic patients. Material and Methods: In a pilot study, eight patients with low HDL (≤ 40 mg/dL) were treated with extended release nicotinic acid. HDL cholesterol and phospholipid levels, HDL2 and HDL3 fractions and HDL particle sizes were measured at baseline and post-therapy. Before and after nicotinic acid treatment, HDL particles were used for cholesterol transport studies in cells transfected with SR-BI. Results: Nicotinic acid treatment raised total HDL cholesterol and phospholipids, HDL2 levels as well as HDL particle size. Nicotinic acid significantly increased HDL cholesterol efflux and uptake capacity mediated by SR-BI in cultured cells. Conclusions: Nicotinic acid therapy increases SR-BI-dependent HDL cholesterol transport in cultured cells, establishing a new cellular mechanism by which this lipid-lowering drug appears to modulate HDL metabolism in patients with hypoalphalipoproteinemia.

Independent anti-angiogenic capacities of coagulation factors X and Xa.

Knockout models have shown that the coagulation system has a role in vascular development and angiogenesis. Herein, we report for the first time that zymogen FX and its active form (FXa) possess anti-angiogenic properties. Both the recombinant FX and FXa inhibit angiogenesis in vitro using endothelial EA.hy926 and human umbilical cord vascular endothelial cells (HUVEC). This effect is dependent on the Gla domain of FX. We demonstrate that FX and FXa use different mechanisms: the use of Rivaroxaban (RX) a specific inhibitor of FXa attenuated its anti-angiogenic properties but did not modify the anti-angiogenic effect of FX. Furthermore, only the anti-angiogenic activity of FXa is PAR-1dependent. Using in vivo models, we show that FX and FXa are anti-angiogenic in the zebrafish intersegmental vasculature (ISV) formation and in the chick embryo chorioallantoic membrane (CAM) assays. Our results provide further evidence for the non-hemostatic functions of FX and FXa and demonstrate for the first time a biological role for the zymogen FX.

Exfoliative cytology of oral epithelial cells from patients with type 2 diabetes: cytomorphometric analysis.

This research objective is to identify cytomorphometrical changes using exfoliative cytology (EC) and later Papanicolaou (Pap) staining, for oral epithelial cells of patients with type 2 diabetes (DM2) (n = 30), while being compared to patients without the disease (n = 30). Additionally, we investigated an association between cellular changes and salivary flow levels; relationship that until now has not been reported. Results show that the cell diameter and the nuclear-cytoplasmic ratio was significantly higher compared to those patients without the disease (p ≤ 0.001 Student and Welch test). Decreased salivary flow was significantly associated with increased cell diameter and nuclear-cytoplasmic ratio (p ≤ 0.001 ANOVA with Tukey test). Evidence and clinical observations show that DM2 and decreased salivary flow are related to detectable cytomorphometrical changes in exfoliated cells, which may extend the horizon of this cytological technique.