RESUMEN
After developing a blood disorder, Yale Nemerson became interested in hematology. This led to his lifelong study of thrombogenic tissue factor and to his contributions to developing the modern theory of blood coagulation. The two Classic papers reprinted here detail some of Nemerson's studies on coagulation factors IX and VII.
Asunto(s)
Coagulación Sanguínea , Factor IX/metabolismo , Factor VII/metabolismo , Enfermedades Hematológicas/metabolismo , Hematología/historia , Tromboplastina/metabolismo , Animales , Factor IX/historia , Factor VII/historia , Enfermedades Hematológicas/historia , Historia del Siglo XX , Humanos , Tromboplastina/historiaAsunto(s)
Bioquímica/historia , Fosforilación/fisiología , Animales , Historia del Siglo XX , HumanosAsunto(s)
Productos Biológicos/biosíntesis , Mercurio/metabolismo , Oxidorreductasas/metabolismo , S-Acetiltransferasa de la Proteína Transportadora de Grupos Acilo/metabolismo , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Oxidorreductasas/aislamiento & purificación , Pseudomonas aeruginosa/metabolismoAsunto(s)
Bioquímica/historia , Enzimas de Restricción del ADN/metabolismo , Haemophilus influenzae/enzimología , Bacteriófago P22/genética , Metilasas de Modificación del ADN/metabolismo , Desoxirribonucleasas/metabolismo , Genoma Humano , Haemophilus influenzae/genética , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Plásmidos , Análisis de Secuencia de ADN , Estados UnidosAsunto(s)
Biología Molecular/historia , Anticuerpos Monoclonales , Centrifugación por Gradiente de Densidad , Cromatografía de Afinidad , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Cromatografía por Intercambio Iónico , Durapatita , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Hidroxiapatitas , Cinética , Sustancias Macromoleculares , Peso Molecular , Factores de Iniciación de Péptidos/aislamiento & purificación , Factores de Iniciación de Péptidos/metabolismo , Retratos como Asunto , Conformación Proteica , ARN Polimerasa II/aislamiento & purificación , ARN Polimerasa II/metabolismo , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Moldes Genéticos , Factores de Transcripción/aislamiento & purificación , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
During endotoxemia, liver microcirculation disruption is characterized by a hypersensitivity to the constrictor effects of endothelin 1 (ET-1). The shift of ET-1-mediated effects toward vasoconstriction may result from depressed ET-1-mediated vasodilation through decreased ET-1-induced nitric oxide (NO) production. We have previously shown that lipopolysaccharide (LPS) pretreatment abrogates ET-1-induced endothelial nitric oxide synthase (eNOS) translocation, but its effects on eNOS activation are yet to be determined. Our aim was to assess the effects of LPS on ET-1-mediated eNOS activation in hepatic sinusoidal endothelial cells (SECs) and to investigate the molecular mechanisms involved. SECs were treated with LPS (100 ng/mL) for 6 hours followed by 30 minutes ET-1 (10 nmol/L) stimulation. LPS significantly inhibited ET-1-mediated eNOS activation. This inhibition was associated with upregulation of Caveolin-1 (CAV-1) and a shift in ET-1-mediated eNOS phosphorylation from an activation (Ser1177) to an inhibition (Thr495). LPS treatment has been shown to induce ET-1 expression and secretion from endothelial cells. We therefore investigated the role of endogenous ET-1 in the inhibition of ET-1 activation of eNOS after LPS. Antagonizing ET-1 effects and blocking its activation in LPS pretreated SECs decreased the LPS-induced overexpression of CAV-1 as well as the inhibition of ET-1-induced NOS activity. Furthermore, 6 hours of ET-1 treatment exerted the same effects on eNOS activity, phosphorylation, and CAV-1 expression as LPS treatment. In conclusion, LPS-induced suppression of ET-1-mediated eNOS activation is ET-1 dependent and suggest a pivotal role of CAV-1 in eNOS induction inhibition under stress.