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1.
Eur J Clin Pharmacol ; 67(9): 877-83, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21445638

RESUMEN

PURPOSE: The pathogenic role of angiotensin-converting enzyme (ACE) inhibition in hypertensive patients regarding endothelial progenitor-cell (EPC) function is still poorly understood. The aim of the study was to evaluate EPC number, function, and relationship to carotid intima media thickness (IMT) progression. METHODS: We studied 36 newly diagnosed mildly hypertensive patients free of cardiovascular disease and related risk factors without prior or concurrent therapy with ACE inhibitors. Patients were randomized to receive enalapril 20 mg/day (n = 18) or zofenopril 30 mg/day (n = 18). EPC number and migrating capacity, plasma nitrite and nitrate (NOx), and isoprostane concentrations were evaluated. Carotid IMT was determined by ultrasonography at baseline and after 1 and 5 years of follow-up. RESULTS: EPC number increased during the follow-up, with no statistical differences between treatment groups. There was an inverse correlation between circulating EPCs and IMT increase over time. Plasma NOx decreased during the study without evident differences between treatment groups. Isoprostanes decreased more markedly in zofenopril-treated patients. Multiple linear regression model demonstrated that carotid IMT was significantly inversely correlated with EPC but not with migratory cells after adjusting for confounders. CONCLUSIONS: The study demonstrated that EPC levels increased during the follow-up in both groups of newly diagnosed hypertensive patients treated with ACE inhibitors. These drugs prevented progression of vascular damage, with an inverse correlation between circulating EPC levels and IMT values.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Captopril/análogos & derivados , Arterias Carótidas/patología , Movimiento Celular/efectos de los fármacos , Enalapril/uso terapéutico , Hipertensión/tratamiento farmacológico , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Captopril/administración & dosificación , Captopril/uso terapéutico , Arterias Carótidas/diagnóstico por imagen , Recuento de Células , Células Cultivadas , Enalapril/administración & dosificación , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Estudios de Seguimiento , Humanos , Hipertensión/sangre , Hipertensión/patología , Isoprostanos/sangre , Persona de Mediana Edad , Nitratos/sangre , Nitritos/sangre , Análisis de Regresión , Células Madre/citología , Células Madre/efectos de los fármacos , Resultado del Tratamiento , Túnica Íntima/diagnóstico por imagen , Túnica Íntima/patología , Ultrasonografía
2.
Proc Natl Acad Sci U S A ; 105(27): 9427-32, 2008 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-18595894

RESUMEN

The recruitment of circulating endothelial progenitor cells (EPCs) might have a beneficial effect on the clinical course of several diseases. Endothelial damage and detachment of endothelial cells are known to occur in infection, tissue ischemia, and sepsis. These detrimental effects in EPCs are unknown. Here we elucidated whether human EPCs internalize Bartonella henselae constituting a circulating niche of the pathogen. B. henselae invades EPCs as shown by gentamicin protection assays and transmission electron microscopy (TEM). Dil-Ac-LDL/lectin double immunostaining and fluorescence-activated cell sorting (FACS) analysis of EPCs revealed EPC bioactivity after infection with B. henselae. Nitric oxide (NO) and its precursor l-arginine (l-arg) exert a plethora of beneficial effects on vascular function and modulation of immune response. Therefore, we tested also the hypothesis that l-arg (1-30 mM) would affect the infection of B. henselae or tumor necrosis factor (TNF) in EPCs. Our data provide evidence that l-arg counteracts detrimental effects induced by TNF or Bartonella infections via NO (confirmed by DETA-NO and L-NMMA experiments) and by modulation of p38 kinase phosphorylation. Microarray analysis indicated several genes involved in immune response were differentially expressed in Bartonella-infected EPCs, whereas these genes returned in steady state when cells were exposed to sustained doses of l-arg. This mechanism may have broad therapeutic applications in tissue ischemia, angiogenesis, immune response, and sepsis.


Asunto(s)
Arginina/farmacología , Bartonella henselae/efectos de los fármacos , Células Endoteliales/microbiología , Óxido Nítrico/farmacología , Células Madre/microbiología , Adhesión Bacteriana/efectos de los fármacos , Bartonella henselae/citología , Bartonella henselae/ultraestructura , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales/enzimología , Células Endoteliales/ultraestructura , Activación Enzimática/efectos de los fármacos , Citometría de Flujo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células Madre/citología , Células Madre/enzimología , Células Madre/ultraestructura , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
3.
Atherosclerosis ; 209(2): 403-14, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19932479

RESUMEN

OBJECTIVE: Peripheral arterial disease (PAD) is a major health problem especially when associated to concomitant diabetes and hypercholesterolemia. Hyperglycemia with an overwhelming generation of oxygen radicals and formation of glycation end-products exacerbates oxidation-sensitive mechanisms activated by tissue ischemia. Administration of autologous bone marrow cells (BMC) is an increasing notable intervention to induce therapeutic angiogenesis, ameliorated by metabolic intervention (MT). Recently, hemangioblasts (HS) with functional properties were isolated. METHODS: The effects of integrate regimen with intravenous BMC, HS, and MT (1.0% vitamin E, 0.05% vitamin C, and 6% l-arginine) were examined in the ischemic hindlimb of ApoE(-/-) diabetic and non-diabetic. Blood flow ratio was monitored by use of a laser Doppler blood flowmeter. Capillary density was determined in sections of the adductor and semimembranous muscles with antibody against CD31. RESULTS: BMC or HS alone, and BMC plus HS increased blood flow and capillary densities and decreased interstitial fibrosis. These effects were amplified by additional MT, at least in part, through the nitric oxide pathway, reduction of systemic oxidative stress and macrophage infiltration. Investigation of molecular mechanisms in bone marrow (BM)-derived progenitor cells from mice revealed that BMC therapy and, more consistently, in combination with MT ameliorated functional activity via decreased cellular senescence and increased telomerase and chemokine CXCR4 activities. Telomerase activity was also increased by HS alone or HS+MT and, more consistently, by BMC+HS alone or in combination with MT. CONCLUSIONS/INTERPRETATION: Intravenous autologous BMC and HS intervention together with MT increased therapeutic angiogenesis in the ApoE(-/-) diabetic mouse hindlimb.


Asunto(s)
Trasplante de Médula Ósea , Diabetes Mellitus Experimental/terapia , Hemangioblastos/trasplante , Miembro Posterior/irrigación sanguínea , Neovascularización Fisiológica/fisiología , Enfermedades Vasculares Periféricas/terapia , Animales , Apolipoproteínas E/deficiencia , Arginina/uso terapéutico , Ácido Ascórbico/uso terapéutico , Isquemia/terapia , Ratones , Flujo Sanguíneo Regional , Vitamina E/uso terapéutico
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