Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver.

OBJECTIVE: The transcription factor Kruppel-like factor 2 (KLF2) modulates the expression of multiple endothelial vasoprotective genes. In the absence of KLF2, the endothelial phenotype becomes dysfunctional. To date, blood-derived shear stress is the main physiological stimulus identified to trigger and sustain endothelial KLF2 expression. Portal hypertension is a common complication of cirrhosis. Sinusoidal distortion and endothelial dysfunction play a significant role in its pathogenesis. This study aimed to assess whether abnormal intrahepatic haemodynamics in cirrhosis could modify KLF2 expression and consequently its downstream transcriptional programmes. DESIGN: Rats received carbon tetrachloride or vehicle for two (acute injury), six (early cirrhosis) and twelve weeks (advanced cirrhosis). Systemic and hepatic haemodynamic parameters were measured in vivo. Hepatic expression of KLF2 and its vasoprotective targets were determined. Additionally, KLF2 expression was determined in liver sections, in freshly-isolated hepatic endothelial cells, and in livers from simvastatin-treated cirrhotic animals. RESULTS: Cirrhotic livers have increased endothelial KLF2 expression compared with controls. KLF2 elevation, observed at six weeks of cirrhosis induction, was accompanied by a parallel increase in portal pressure and an increase in the expression of its target genes eNOS, thrombomodulin and CNP. Simvastatin administration further increased hepatic KLF2 and target genes expression. CONCLUSIONS: This study shows an increase in the expression of the vasoprotective transcription factor KLF2 in the cirrhotic liver, accompanied by an activation of its downstream transcriptional programmes. These data suggest that the marked increase in KLF2 expression may represent an endothelial compensatory mechanism to improve the ongoing vascular dysfunction in the cirrhotic liver. [ABSTRACT FROM AUTHOR]