RESUMO
BACKGROUND: Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to modulate endothelial function, the transcriptional mechanisms underlying these effects are incompletely understood. We hypothesized that Lung-Kruppel-like factor (LKLF/KLF2), a novel and potent regulator of endothelial gene expression, may mediate the downstream effects of statins. Here we report that statin-induced expression of endothelial NO synthase (eNOS) and thrombomodulin is KLF2 dependent. METHODS AND RESULTS: KLF2 mRNA was induced by treatment with multiple statins in a concentration-dependent manner. Multiple lines of evidence suggest that this induction is dependent on inhibition of the Rho pathway and requires de novo transcription. Furthermore, promoter deletion and mutational analyses suggest that mevastatin induced KLF2 promoter activity through a single myocyte enhancer factor binding site. Finally, small-interfering RNA-mediated knockdown of KLF2 strongly attenuated the ability of mevastatin to increase eNOS and thrombomodulin accumulation in endothelial cells. CONCLUSIONS: Taken together, these observations indicate that statin-dependent induction of eNOS and thrombomodulin requires KLF2 and thereby provides a novel molecular target for modulating endothelial function in vascular disease.
Assuntos
Endotélio Vascular/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fatores de Transcrição Kruppel-Like/genética , Regiões 5' não Traduzidas/genética , Sequência de Bases , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Fatores de Transcrição Kruppel-Like/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Proteínas Recombinantes de Fusão/metabolismo , Trombomodulina/genética , Transfecção , Veias UmbilicaisRESUMO
We investigated gender differences in the prescription of prophylaxis against deep vein thrombosis (DVT) in 2,619 patients who developed acute DVT while being hospitalized for reasons other than DVT or were diagnosed with acute DVT as outpatients but who had been hospitalized within 30 days prior to DVT diagnosis. Men were 21% more likely than women to receive prophylaxis (OR 1.21, 95% CI 1.03-1.43; p=0.021) after adjusting for DVT risk factors, including surgery, trauma, prior DVT, age, and cancer.
Assuntos
Preconceito , Pré-Medicação/estatística & dados numéricos , Trombose Venosa/prevenção & controle , Doença Aguda , Coleta de Dados , Feminino , Hospitalização , Humanos , Masculino , Fatores Sexuais , Trombose Venosa/tratamento farmacológicoRESUMO
The Kruppel-like factor KLF2 was recently identified as a novel regulator of endothelial pro-inflammatory and pro-thrombotic function. Here it is shown that overexpression of KLF2 potently inhibits vascular permeability factor/vascular endothelial growth factor (VEGF-A)-mediated angiogenesis and tissue edema in the nude ear mouse model of angiogenesis. In vitro, KLF2 expression retards VEGF-mediated calcium flux, proliferation and induction of pro-inflammatory factors in endothelial cells. This effect is due to a potent inhibition of VEGFR2/KDR expression and promoter activity. These observations identify KLF2 as a regulator of VEGFR2/KDR and provide a foundation for novel approaches to regulate angiogenesis.