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1.
Circulation ; 111(22): 2981-7, 2005 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-15927972

RESUMEN

BACKGROUND: The maintenance of endothelial integrity plays a critical role in preventing atherosclerotic disease progression. Endothelial progenitor cells (EPCs) were experimentally shown to incorporate into sites of neovascularization and home to sites of endothelial denudation. Circulating EPCs may thus provide an endogenous repair mechanism to counteract ongoing risk factor-induced endothelial injury and to replace dysfunctional endothelium. METHODS AND RESULTS: In 120 individuals (43 control subjects, 44 patients with stable coronary artery disease, and 33 patients with acute coronary syndromes), circulating EPCs were defined by the surface markers CD34+KDR+ and analyzed by flow cytometry. Cardiovascular events (cardiovascular death, unstable angina, myocardial infarction, PTCA, CABG, or ischemic stroke) served as outcome variables over a median follow-up period of 10 months. Patients suffering from cardiovascular events had significantly lower numbers of EPCs (P<0.05). Reduced numbers of EPCs were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis (P=0.0009). By multivariate analysis, reduced EPC levels were a significant, independent predictor of poor prognosis, even after adjustment for traditional cardiovascular risk factors and disease activity (hazard ratio, 3.9; P<0.05). CONCLUSIONS: Reduced levels of circulating EPCs independently predict atherosclerotic disease progression, thus supporting an important role for endogenous vascular repair to modulate the clinical course of coronary artery disease.


Asunto(s)
Vasos Sanguíneos/fisiología , Enfermedades Cardiovasculares/diagnóstico , Células Endoteliales/citología , Valor Predictivo de las Pruebas , Regeneración , Células Madre/citología , Adulto , Anciano , Angina de Pecho/sangre , Antígenos CD34/análisis , Aterosclerosis/etiología , Recuento de Células Sanguíneas , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/sangre , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/análisis
2.
Exp Dermatol ; 13(2): 78-85, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15009100

RESUMEN

Even though anthralin is a well-established topical therapeutic agent for psoriasis, little is known about its effects and biochemical mechanisms of signal transduction. In contrast to a previous report, we found that anthralin induced time- and concentration-dependent phosphorylation of epidermal growth factor receptor in primary human keratinocytes. Four lines of evidence show that this process is mediated by reactive oxygen species. First, we found that anthralin induces time-dependent generation of H(2)O(2). Second, there is a correlation between a time-dependent increase in anthralin-induced epidermal growth factor receptor phosphorylation and H(2)O(2) generation. Third, the structurally different antioxidants n-propyl gallate and N-acetylcysteine inhibited epidermal growth factor receptor phosphorylation induced by anthralin. Fourth, overexpression of catalase inhibited this process. The epidermal growth factor receptor-specific tyrosine kinase inhibitor PD153035 abrogated anthralin-induced epidermal growth factor receptor phosphorylation and activation of extracellular-regulated kinase 1/2. These findings establish the following sequence of events: (1) H(2)O(2) generation, (2) epidermal growth factor receptor phosphorylation, and (3) extracellular-regulated kinase activation. Our data identify anthralin-induced reactive oxygen species and, more specifically, H(2)O(2) as an important upstream mediator required for ligand-independent epidermal growth factor receptor phosphorylation and downstream signaling.


Asunto(s)
Antralina/farmacología , Antiinflamatorios/farmacología , Receptores ErbB/metabolismo , Peróxido de Hidrógeno/metabolismo , Queratinocitos/fisiología , Acetilcisteína/farmacología , Antioxidantes/farmacología , Catalasa/genética , Catalasa/metabolismo , Células Cultivadas , Electroporación , Receptores ErbB/efectos de los fármacos , Humanos , Queratinocitos/efectos de los fármacos , Cinética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosforilación , Fosfotirosina/metabolismo , Psoriasis/tratamiento farmacológico , Proteínas Recombinantes/metabolismo , Transducción de Señal
3.
Circ Res ; 94(6): 768-75, 2004 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-14963003

RESUMEN

Aging is associated with a rise in intracellular reactive oxygen species (ROS) and a loss of telomerase reverse transcriptase activity. Incubation with H2O2 induced the nuclear export of telomerase reverse transcriptase (TERT) into the cytosol in a Src-family kinase-dependent manner. Therefore, we investigated the hypothesis that age-related increase in reactive oxygen species (ROS) may induce the nuclear export of TERT and contribute to endothelial cell senescence. Continuous cultivation of endothelial cells resulted in an increased endogenous formation of ROS starting after 29 population doublings (PDL). This increase was accompanied by mitochondrial DNA damage and preceded the onset of replicative senescence at PDL 37. Along with the enhanced formation of ROS, we detected an export of nuclear TERT protein from the nucleus into the cytoplasm and an activation of the Src-kinase. Moreover, the induction of premature senescence by low concentrations of H2O2 was completely blocked with the Src-family kinase inhibitor PP2, suggesting a crucial role for Src-family kinases in the induction of endothelial cell aging. Incubation with the antioxidant N-acetylcysteine, from PDL 26, reduced the intracellular ROS formation and prevented mitochondrial DNA damage. Likewise, nuclear export of TERT protein, loss in the overall TERT activity, and the onset of replicative senescence were delayed by incubation with N-acetylcysteine. Low doses of the statin, atorvastatin (0.1 micromol/L), had also effects similar to those of N-acetylcysteine. We conclude that both antioxidants and statins can delay the onset of replicative senescence by counteracting the increased ROS production linked to aging of endothelial cells.


Asunto(s)
Antioxidantes/farmacología , Senescencia Celular/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/citología , Transporte de Proteínas/efectos de los fármacos , Telomerasa/metabolismo , Acetilcisteína/farmacología , Atorvastatina , Núcleo Celular/metabolismo , Células Cultivadas/citología , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , ADN Mitocondrial/análisis , Proteínas de Unión al ADN , Depresión Química , Células Endoteliales/citología , Células Endoteliales/metabolismo , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Ácidos Heptanoicos/farmacología , Humanos , Peróxido de Hidrógeno/farmacología , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Pirimidinas/farmacología , Pirroles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/fisiología
4.
Blood ; 102(4): 1340-6, 2003 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-12702503

RESUMEN

Increasing evidence suggests that postnatal neovascularization involves the recruitment of circulating endothelial progenitor cells (EPCs). Hematopoietic and endothelial cell lineages share common progenitors. Cytokines formerly thought to be specific for the hematopoietic system have only recently been shown to affect several functions in endothelial cells. Accordingly, we investigated the stimulatory potential of erythropoietin (Epo) on EPC mobilization and neovascularization. The bone marrow of Epo-treated mice showed a significant increase in number and proliferation of stem and progenitor cells as well as in colony-forming units. The number of isolated EPCs and CD34+/flk-1+ precursor cells was significantly increased in spleen and peripheral blood of Epo-treated mice compared with phosphate-buffered saline-treated mice. In in vivo models of postnatal neovascularization, Epo significantly increased inflammation- and ischemia-induced neovascularization. The physiologic relevance of these findings was investigated in patients with coronary heart disease. In a multivariate regression model, serum levels of Epo and vascular endothelial growth factor were significantly associated with the number of stem and progenitor cells in the bone marrow as well as with the number and function of circulating EPCs. In conclusion, the present study suggests that Epo stimulates postnatal neovascularization at least in part by enhancing EPC mobilization from the bone marrow. Epo appears to physiologically regulate EPC mobilization in patients with ischemic heart disease. Thus, Epo serum levels may help in identifying patients with impaired EPC recruitment capacity.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Eritropoyetina/farmacología , Neovascularización Fisiológica/fisiología , Células Madre/efectos de los fármacos , Células Madre/fisiología , Animales , Antígenos CD34/metabolismo , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Recuento de Células , División Celular/efectos de los fármacos , División Celular/fisiología , Movimiento Celular/fisiología , Enfermedad Coronaria/sangre , Factores de Crecimiento Endotelial/sangre , Eritropoyetina/sangre , Eritropoyetina/fisiología , Miembro Posterior/irrigación sanguínea , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Isquemia/inducido químicamente , Isquemia/metabolismo , Linfocinas/sangre , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/efectos de los fármacos , Proteínas Recombinantes/farmacología , Células Madre/citología , Factor A de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular
5.
Arterioscler Thromb Vasc Biol ; 22(1): 69-75, 2002 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11788463

RESUMEN

Endothelial cell (EC) migration is required for angiogenesis, neovascularization, and reendothelialization. Integrins, known as alphabeta-heterodimeric cell-surface receptors, regulate cell migration and are essential for mechanotransduction of hemodynamic forces. Therefore, we investigated the effect of shear stress on EC migration and the contribution of the integrins and integrin-dependent signaling pathways in a scratched-wound assay. Laminar shear stress-induced EC migration was significantly reduced by integrin-receptor blocking with RGD peptides or with neutralizing antibodies against integrin subunits alpha(5) and beta(1), whereas antibodies against alpha(v)beta(3) or alpha(2)beta(1) had no effect. Cell-surface levels of the integrin alpha(5) and beta(1) were specifically upregulated in migrating ECs at the wound edges. Consistent with the important role of integrins for shear stress-increased cell migration, blockade of the integrin-associated adapter protein Shc by overexpression of dominant negative construct inhibited shear stress-stimulated EC migration. Moreover, pharmacological inhibition of the integrin downstream effector signaling molecules ERK1/2 or phosphatidyl-inositol-3-kinase prevented shear stress-induced EC migration. In contrast, inhibition of the NO synthase had no effect. Taken together, our results indicate that laminar shear stress enhances EC migration via the fibronectin receptor subunits alpha(5) and beta(1), which serve as central mechanotransducers in ECs. Shear stress-induced enhancement of EC migration might contribute importantly to accelerated reendothelialization of denuded arteries.


Asunto(s)
Movimiento Celular/fisiología , Endotelio Vascular/fisiología , Hemorreología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Receptores de Fibronectina/fisiología , Receptores de Vitronectina/fisiología , Células Cultivadas , Endotelio Vascular/citología , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Humanos , Fosforilación , Transducción de Señal , Venas Umbilicales/citología , Regulación hacia Arriba
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