The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins

详细信息    查看全文

• 作者：Giusi Marrone¹ ; ^&dagger ; ; Lucia Russo¹ ; ^&dagger ; ; Eugenio Rosado¹ ; Diana Hide¹ ; Guillermo Garcí ; a-Cardeñ ; a² ; Juan Carlos Garcí ; a-Pagá ; n¹ ; Jaime Bosch¹ ; ^{jbosch@clinic.ub.es} ; Jorge Gracia-Sancho¹ ; ^{jgracia@clinic.ub.es}
• 关键词：KLF2 ; Kruppel-like factor 2 ; eNOS ; endothelial nitric oxide synthase ; SEC ; sinusoidal endothelial cells ; HSC ; hepatic stellate cells ; CCl4 ; carbon tetrachloride ; VEGF ; vascular endothelial growth factor ; ¦Á-SMA ; alpha smooth muscle actin ; IVR ; intrahepati
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：58
• 期：1
• 页码：98-103
• 全文大小：673 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Background & Aims

Statins improve hepatic endothelial function and liver fibrosis in experimental models of cirrhosis, thus they have been proposed as therapeutic options to ameliorate portal hypertension syndrome. The transcription factor Kruppel-like factor 2 (KLF2) may be induced by statins in liver sinusoidal endothelial cells (SEC), orchestrating an efficient vasoprotective response. The present study aimed at characterizing whether KLF2 mediates statins-derived hepatic protection.

Methods

Expression of KLF2 and its vasoprotective target genes was determined in SEC freshly isolated from control or CCl₄-cirrhotic rats treated with four different statins (atorvastatin, mevastatin, simvastatin, and lovastatin), in the presence of mevalonate (or vehicle), under static or controlled shear stress conditions. KLF2-derived vasoprotective transcriptional programs were analyzed in SEC transfected with siRNA for KLF2 or siRNA-control, and incubated with simvastatin. Paracrine effects of SEC highly-expressing KLF2 on the activation status of rat and human hepatic stellate cells (HSC) were evaluated.

Results

Statins administration to SEC induced significant upregulation of KLF2 expression. KLF2 upregulation was observed after 6 h of treatment and was accompanied by induction of its vasoprotective programs. Simvastatin vasoprotection was inhibited in the presence of mevalonate, and was magnified in cells cultured under physiological shear stress conditions. Statin-dependent induction of vasoprotective genes was not observed when KLF2 expression was muted with siRNA. SEC overexpressing KLF2 induced quiescence of HSC through a KLF2-nitric oxide-guanylate cyclase-mediated paracrine mechanism.

Conclusions

Upregulation of hepatic endothelial KLF2-derived transcriptional programs by statins confers vasoprotection and stellate cells deactivation, reinforcing the therapeutic potential of these drugs for liver diseases that course with endothelial dysfunction.