Submitted on July 8, 2004
Accepted on November 13, 2004
SINUSOIDAL ENDOTHELIAL COX-1 DERIVED PROSTANOIDS MODULATE THE HEPATIC VASCULAR TONE OF CIRRHOTIC RAT LIVERS
Mariona Graupera1, Sandra March2, Pablo Engel2, Juan Rodes1, Jaume Bosch1, and Joan-Carles Garcia-Pagan1*
1 Hepatic Hemodynamic Laboratory, Liver Unit. Institut Malalties Digestives, University of Barcelona, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2 Immunology Unit, Department of Cellular Biology and Pathology, University of Barcelona, IDIBAPS, Medical School, Barcelona, Spain
* To whom correspondence should be addressed. E-mail: jcgarcia{at}clinic.ub.es.
Background/: CCl4 cirrhotic rat liver exhibits a hyperesponse to the 
1-
adrenergic agonist, methoxamine (Mtx) that is associated with enhanced
thromboxane A2 (TXA2) production and is abrogated by Indomethacin.
Aim/Methods: To further elucidate the molecular mechanisms involved in the
hyperresponse to vasoconstrictors, portal perfusion pressure (PP) dose-response
curves to Mtx were performed in CCl4 cirrhotic rats livers after
preincubation with vehicle, the cyclooxygenase-1 (COX-1) selective inhibitor
SC-560 and the cyclooxygenase-2 (COX-2) selective inhibitor SC-236. TXA2
production was determined in samples of the perfusate. COX-1 expression was
analyzed and quantified in hepatocytes, Kupffer cells, sinusoidal endothelial
cells (SEC) and hepatic stellate cells (HSC) isolated from control and cirrhotic
rat livers by double immunofluorescence staining with specific markers for each
population using flow cytometry or Western blot. Results: COX-1 protein levels
were not significantly increased in cirrhotic livers, but COX-2 protein expression
was increased. COX-1 inhibition, but not COX-2, significantly attenuated the
response to Mtx, and prevented the increased production of TXA2. Cirrhotic
livers showed an increased expression of COX-1 in SEC and reduced
expression in HSC in comparison to control livers, while COX-1 was similarly
distributed in Kupffer cells. Conclusion: Despite abundant hepatic COX-2
expression, the increased response to Mtx of cirrhotic livers is mainly
dependent of COX-1. Up-regulation of COX-1 in cirrhotic SEC may be
responsible for the hyperesponse to Mtx.
