RESUMO
Krüppel-like factor 4 (KLF4) is a transcription factor expressed in the vascular endothelium, where it promotes anti-inflammatory and anticoagulant states, and increases endothelial nitric oxide synthase expression. We examined the role of endothelial KLF4 in pulmonary arterial (PA) hypertension (PAH). Mice with endothelial KLF4 knockdown were exposed to hypoxia for 3 weeks, followed by measurement of right ventricular and PA pressures, pulmonary vascular muscularization, and right ventricular hypertrophy. The effect of KLF4 on target gene expression was assessed in lungs from these mice, verified in vitro by small interfering RNA (siRNA) knockdown of KLF4, and further studied at the promoter level with cotransfection experiments. KLF4 expression was measured in lung tissue from patients with PAH and normal control subjects. We found that, after hypoxia, right ventricular and PA pressures were significantly higher in KLF4 knockdown animals than controls. Knockdown animals also had more severe pulmonary vascular muscularization and right ventricular hypertrophy. KLF4 knockdown resulted in increased pulmonary expression of endothelin-1 and decreased expression of endothelial nitric oxide synthase, endothelin receptor subtype B, and prostacyclin synthase. Concordant findings were observed in vitro, both with siRNA knockdown of KLF4 and promoter activity assays. Finally, KLF4 expression was reduced in lungs from patients with PAH. In conclusion, endothelial KLF4 regulates the transcription of genes involved in key pathways implicated in PAH, and its loss exacerbates pulmonary hypertension in response to chronic hypoxia in mice. These results introduce a novel transcriptional modulator of PAH, with the potential of becoming a new therapeutic target.
Assuntos
Pressão Arterial , Células Endoteliais/metabolismo , Hipertensão Pulmonar/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Artéria Pulmonar/metabolismo , Animais , Estudos de Casos e Controles , Células Cultivadas , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Endotelina-1/metabolismo , Hipertensão Pulmonar Primária Familiar , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Hipóxia/complicações , Oxirredutases Intramoleculares/metabolismo , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Interferência de RNA , Receptor de Endotelina B/metabolismo , Fatores de Tempo , Transfecção , Função Ventricular Direita , Pressão VentricularRESUMO
We report an interesting case of a 65-year-old gentleman who presented with hypertensive emergency and was found to have an isolated spontaneous dissection of the right renal artery. The dissection was stented via endovascular approach and resulted in marked improvement in blood pressure. Spontaneous renal artery dissection is a difficult condition to diagnose and treat, unless suspected early enough during the course of treatment. Endovascular intervention is the treatment of choice, as failure of conservative treatment may have long lasting clinical implications relating to decreased renal perfusion. Surgical intervention can be associated with high rate of complications.
