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Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver
  1. Jorge Gracia-Sancho1,2,
  2. Lucia Russo1,
  3. Héctor García-Calderó1,
  4. Joan Carles García-Pagán1,
  5. Guillermo García-Cardeña2,
  6. Jaime Bosch1
  1. 1Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic–IDIBAPS, University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
  2. 2Laboratory for Systems Biology, Center for Excellence in Vascular Biology, Departments of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Jaime Bosch, Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic i Provincial, Villarroel 170, 08036 Barcelona, Spain; jbosch{at}clinic.ub.es

Abstract

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.

  • Endothelial cells
  • endothelial dysfunction
  • endothelium
  • eNOS
  • gene expression
  • KLF2
  • nitric oxide
  • portal hypertension
  • statins

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Footnotes

  • Funding JGS was supported by the Spanish Association for the Study of the Liver (AEEH) and the Catalan Digestology Society (SCD). The study was supported by grants from Instituto de Salud Carlos III (PI06-0623 and PI09-01261), Ministerio de Educación y Ciencia (SAF 07/61298) and NIH (HL-076686 and HL-090856). CIBERehd is funded by the Instituto de Salud Carlos III.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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