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Hypoxia and proinflammatory factors upregulate apelin receptor expression in human stellate cells and hepatocytes
  1. Pedro Melgar-Lesmes1,
  2. Montserrat Pauta1,
  3. Vedrana Reichenbach1,
  4. Gregori Casals1,
  5. Josefa Ros1,
  6. Ramon Bataller2,3,
  7. Manuel Morales-Ruiz1,3,
  8. Wladimiro Jiménez1,3,4
  1. 1Service of Biochemistry and Molecular Genetics, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
  2. 2Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
  3. 3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
  4. 4Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain
  1. Correspondence to Dr Wladimiro Jiménez, Servicio de Bioquímica y Genética Molecular, Hospital Clinic Universitari, Villarroel 170, Barcelona 08036, Spain; wjimenez{at}


Background The activation of the apelin receptor (APJ) plays a major role in both angiogenic and fibrogenic response to chronic liver injury. However, the mechanisms that govern the induction of APJ expression have not been clarified so far.

Methods The regulation and the role of APJ in cultured human liver cells were investigated. Tissular expression of APJ and α-smooth muscle actin was analysed by immunocolocalisation in human cirrhotic liver and in control samples. mRNA and protein expression of APJ were analysed in two cell lines, LX-2 (as hepatic stellate cells, HSCs) and HepG2 (as hepatocytes), under hypoxic conditions or after exposure to proinflammatory or profibrogenic factors. Additionally, both hepatic cell lines were stimulated with apelin to assess cell survival and the expression of angiogenic factors.

Results The APJ-positive signal was negligible in control livers. In contrast, APJ was highly expressed in HSCs and slightly expressed in hepatocytes of human cirrhotic liver. Sustained hypoxia and lipopolysaccharide stimulated the expression of APJ in LX-2 cells. Moreover, hypoxia, tumour necrosis factor α and angiotensin II induced the expression of APJ in HepG2 cells. Activation of APJ stimulated angiopoietin-1 expression and cell survival in LX-2 cells and, in turn, triggered the synthesis of vascular endothelial growth factor type A and platelet-derived growth factor-BB in HepG2 cells.

Conclusions These results suggest that hypoxia and inflammatory factors could play a major role in the activation of the hepatic apelin system leading to angiogenic and fibroproliferative response occurring in chronic liver disease.

  • Angiogenesis
  • cirrhosis
  • growth factors
  • inflammation

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  • Funding This work was supported by grants from the Dirección General de Investigación Científica y Técnica (SAF06-07053 and SAF09-08839 to WJ and SAF07-63069 to MM-R) and from the Agència de Gestió d'Ajuts Universitaris I de Recerca (SGR 2009/1496). PM-L had a grant from DGICYT (BES-2004-5186 and SAF07-63069). GC is a recipient of a ‘Contrato post formación sanitaria especializada’ from the Instituto de Salud Carlos III (FIS CM07/00043). MP had a grant from DGICYT (BES-2007-16906). CIBERehd is funded by the Instituto de Salud Carlos III (Spain).

  • Competing interests None.

  • Ethics approval The study was performed according to the criteria of the Investigation and Ethics Committee of the Hospital Clínic Universitari.

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

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