Asunto(s)
Aneurisma de la Aorta Abdominal/cirugía , Arteria Ilíaca/cirugía , Procedimientos Quirúrgicos Vasculares/normas , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Manejo de la Enfermedad , Femenino , Humanos , Arteria Ilíaca/diagnóstico por imagen , Masculino , Complicaciones Posoperatorias/prevención & control , Proyectos de InvestigaciónRESUMEN
Since previous studies have reported a beneficial effect of amlodipine and atorvastatin treatment in experimental atherosclerosis, we aimed to investigate the effect of the combination of both drugs on blood and plaque inflammation in patients with carotid stenosis. For that purpose, twenty six hypertensive patients undergoing carotid endarterectomy were randomized to receive either atorvastatin 20 mg/day alone (ATV, n=12) or in combination with amlodipine 20 mg/day (ATV+AML, n=14) before scheduled carotid endarterectomy. At the end of follow-up (4-6 weeks), there was a significant decrease in total and LDL-cholesterol levels, but not in blood pressure levels. In contrast, decreased MCP-1 plasma levels, NF-kappaB activation (EMSA) and MCP-1 mRNA expression (quantitative PCR) was only observed in blood from ATV+AML treated-patients. Moreover, carotid atherosclerotic plaques from ATV+AML group demonstrated a significant reduction in macrophage infiltration in relation to ATV group (immunohistochemistry). Our results suggest that combined treatment with atorvastatin and amlodipine decreases inflammatory status of atherosclerotic patients more than atorvastatin treatment alone, suggesting that co-administration of both drugs could have beneficial additive effects.
Asunto(s)
Amlodipino/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Estenosis Carotídea/tratamiento farmacológico , Ácidos Heptanoicos/uso terapéutico , Hipertensión/tratamiento farmacológico , Pirroles/uso terapéutico , Anciano , Amlodipino/farmacología , Anticolesterolemiantes/farmacología , Atorvastatina , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/patología , Estenosis Carotídea/sangre , Estenosis Carotídea/patología , Quimiocina CCL2/sangre , LDL-Colesterol/sangre , Sinergismo Farmacológico , Femenino , Ácidos Heptanoicos/farmacología , Humanos , Hipertensión/complicaciones , Macrófagos/patología , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Pirroles/farmacología , ARN Mensajero/metabolismoRESUMEN
Introducción. Entre las diversas estrategias seguidas para analizar la compleja estructura de la placa de ateroma, nuestro grupo se ha centrado en el estudio de las proteínas secretadas por la pared vascular, que podrían ser potenciales marcadores plasmáticos. Las estatinas o los agentes bloqueadores de los canales de calcio (BCC) pueden modular los valores de las proteínas circulantes en sujetos con diversas afecciones cardiovasculares. Métodos. La electroforesis bidimensional y la espectrometría de masas (EM) se han aplicado al estudio de proteínas diferencialmente secretadas por placas de ateroma incubadas ex vivo respecto a zonas fibrosas adyacentes. Asimismo, hemos estudiado el efecto modulador de la atorvastatina (105 M), el amlodipino (106 M) o la combinación de ambos fármacos. Resultados. De una media de 620 proteínas detectadas por gel, se identificaron en total 83 proteínas secretadas por las placas ateromatosas mediante EM: 34 proteínas incrementadas en los sobrenadantes de las placas cultivadas ex vivo respecto a las zonas control y 31 con valores de secreción inferiores en la zona ateromatosa. La adición in vitro de fármacos a las placas de ateroma produjo diferentes efectos en los valores de secreción proteicos, dependiendo del tipo de fármaco y de la proteína considerada, si bien la mayoría de las proteínas identificadas revertía a valores control independientemente del tratamiento. Conclusión. Mediante este análisis proteómico hemos caracterizado nuevas proteínas potencialmente involucradas en la formación e inestabilidad de la placa de ateroma. La modulación por distintos tratamientos farmacológicos de dichos marcadores puede ayudar a comprender nuevos mecanismos de acción de dichos fármacos (AU)
Introduction. Analysis of the complex structure of the atheroma plaque is a classical object of cardiovascular research. We studied proteins secreted by the vascular wall, which could be potential plasma markers. Statins or calcium channel blockers modulate the levels of different circulating proteins in patients with diverse cardiovascular diseases. Methods. Two-dimensional electrophoresis and mass spectrometry were applied to identify and characterize proteins differentially secreted by atheroma plaque samples incubated ex vivo versus adjacent fibrous segments considered as controls. We also analyzed the modulatory effect of atorvastatin (105 M), amlodipine (106 M) and the combination of both drugs. Results. From an average of 620 proteins detected per gel, a total of 83 proteins secreted by atheroma plaque samples were identified by mass spectrometry: 34 proteins were increased in atheroma plaque supernatants versus control segments while 31 showed decreased secretion levels in atheroma plaques. Different effects were detected after in vitro drug administration to complicated atheroma plaques, depending on the kind of drug and protein considered, although the majority of the proteins identified reverted to normal levels independently of the treatment administered. Conclusion. Proteomic analysis characterized a significant number of novel proteins potentially involved in the formation and instability of complicated atherosclerotic plaques. Modulation of these markers by different drugs may help us to understand new potential mechanisms through which these drugs exert their beneficial effects on atherothrombosis (AU)
Asunto(s)
Humanos , Amlodipino/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Proteínas , Proteínas , Arteriosclerosis/metabolismo , Arteriosclerosis/cirugía , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/cirugía , Electroforesis de las Proteínas Sanguíneas , Biomarcadores/análisis , Espectrometría de MasasRESUMEN
Prostaglandin E2 (PGE2), the product of cyclooxygenase-2 (COX-2) and prostaglandin E synthase-1 (mPGES-1), acts through its receptors (EPs) and induces matrix metalloproteinase (MMP) expression, which may favor the instability of atherosclerotic plaques. The effect of statins on EPs expression has not been previously studied. The aim of this study was to investigate the effect of atorvastatin (ATV, 80 mg/d, for one month) on EP expression in plaques and peripheral blood mononuclear cells (PBMC) of patients with carotid atherosclerosis. In addition, we studied the mechanisms by which statins could modulate EPs expression on cultured monocytic cells (THP-1) stimulated with proinflammatory cytokines (IL-1beta and TNF-alpha). Patients treated with atorvastatin showed reduced EP-1 (14 +/- 1.8% versus 26 +/- 2%; P < 0.01), EP-3 (10 +/- 1.5% versus 26 +/- 1.5%; P < 0.05), and EP-4 expression (10 +/- 4.1% versus 26.6 +/- 4.9%; P < 0.05) in atherosclerotic plaques (immunohistochemistry), and EP-3 and EP-4 mRNA expression in PBMC (real time PCR) in relation to non-treated patients. In cultured monocytic cells, atorvastatin (10 micromol/L) reduced EP-1/-3/-4 expression, along with COX-2, mPGES-1, MMP-9, and PGE2 levels elicited by IL-1beta and TNF-alpha. Similar results were noted with aspirin (100 micromol/L), dexamethasone (1 micromol/L), and the Rho kinase inhibitors Y-27632 and fasudil (10 micromol/L both). The effect of atorvastatin was reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. On the whole, we have shown that atorvastatin reduces EPs expression in atherosclerotic plaques and blood mononuclear cells of patients with carotid stenosis and in cultured monocytic cells. The inhibition of EP receptors could explain, at least in part, some of the mechanisms by which statins could modulate the COX-2/mPGES-1 proinflammatory pathway and favor plaque stabilization in humans.
Asunto(s)
Aterosclerosis/tratamiento farmacológico , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Monocitos/efectos de los fármacos , Pirroles/farmacología , Receptores de Prostaglandina E/efectos de los fármacos , Anciano , Aterosclerosis/metabolismo , Atorvastatina , Enfermedades de las Arterias Carótidas/metabolismo , Células Cultivadas , Ciclooxigenasa 2/análisis , Ciclooxigenasa 2/genética , Dinoprostona/análisis , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Oxidorreductasas Intramoleculares/análisis , Oxidorreductasas Intramoleculares/genética , Masculino , Metaloproteinasa 1 de la Matriz/análisis , Ácido Mevalónico/farmacología , Persona de Mediana Edad , Monocitos/química , Prostaglandina-E Sintasas , Proteínas Serina-Treonina Quinasas/fisiología , Receptores de Prostaglandina E/análisis , Proteínas de Unión al GTP rho/fisiología , Quinasas Asociadas a rhoRESUMEN
BACKGROUND AND PURPOSE: To investigate the effect of short-term high-dose atorvastatin on blood and plaque inflammation in patients with carotid stenosis. METHODS: Twenty patients undergoing carotid endarterectomy without previous statin treatment were randomized to receive either atorvastatin 80 mg/d (n=11) or no statins (n=9) for 1 month. We studied inflammatory mediators in plasma (enzyme-linked immunosorbent assay), peripheral blood mononuclear cells (PBMCs; quantitative RT-PCR and EMSA) and plaques (immunohistochemistry and Southwestern histochemistry). RESULTS: Atorvastatin significantly decreased total and low-density lipoprotein cholesterol and prostaglandin E2 plasma levels. PBMCs from treated patients showed impaired NF-kappaB activation and MCP-1 and COX-2 mRNA expression. Carotid atherosclerotic plaques demonstrated a significant reduction in macrophage infiltration, activated NF-kappaB, and COX-2 and MCP-1 expression. CONCLUSIONS: Intensive treatment with atorvastatin decreases inflammatory activity of PBMCs and carotid atherosclerotic plaques in 1 month. These data strongly suggest that the antiinflammatory effect of high doses of statins in humans can be seen very early.