title: PPARα activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor activated by ligands that regulates genes related to vascular tone, oxidative stress, and fibrogenesis, pathways implicated in the development of cirrhosis and portal hypertension. This study aims at evaluating the effects of PPARα activation with fenofibrate on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl(4)-cirrhotic rats.
  
  
  METHODS
  Mean arterial pressure (MAP), portal pressure (PP), and portal blood flow (PBF) were measured in cirrhotic rats treated with oral fenofibrate (25mg/kg/day, n=10) or its vehicle (n=12) for 7 days. The liver was then perfused and dose-relaxation curves to acetylcholine (Ach) were performed. We also evaluated Sirius Red staining of liver sections, collagen-I mRNA expression, and smooth muscle actin (α-SMA) protein expression, cyclo-oxygenase-1 (COX-1) protein expression, and cGMP levels in liver homogenates, and TXB(2) production in perfusates. Nitric oxide (NO) bioavailability and eNOS activation were measured in hepatic endothelial cells (HEC) isolated from cirrhotic rat livers.
  
  
  RESULTS
  CCl(4) cirrhotic rats treated with fenofibrate had a significantly lower PP (-29%) and higher MAP than those treated with vehicle. These effects were associated with a significant reduction in hepatic fibrosis and improved vasodilatory response to acetylcholine. Moreover, a reduction in COX-1 expression and TXB(2) production in rats receiving fenofibrate and a significant increase in NO bioavailability in HEC with fenofibrate were observed.
  
  
  CONCLUSIONS
  PPARα activation markedly reduced PP and liver fibrosis and improved hepatic endothelial dysfunction in cirrhotic rats, suggesting it may represent a new therapeutic strategy for portal hypertension in cirrhosis.
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Spain. Electronic address: arodr@clinic.ub.es.
authors.forename: Aina
authors.initials: A
authors.lastname: Rodríguez-Vilarrupla
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Spain.
authors.forename: Bàrbara
authors.initials: B
authors.lastname: Laviña
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: García-Calderó
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Russo
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Rosado
authors.affiliation: Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Roglans
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Bosch
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Spain.
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: García-Pagán
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002251:Carbon Tetrachloride / Q000009:adverse effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005355:Fibrosis; D006975:Hypertension, Portal / Q000378:metabolism / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D047493:PPAR alpha / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013929:Thromboxane B2 / Q000378:metabolism
chemical_list: D047493:PPAR alpha; D013929:Thromboxane B2; D002251:Carbon Tetrachloride; D051545:Cyclooxygenase 1