Back to Search Start Over

Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats.

Authors :
Schwabl, Philipp
Payer, Berit A.
Grahovac, Jelena
Klein, Sabine
Horvatits, Thomas
Mitterhauser, Markus
Stift, Judith
Boucher, Yves
Trebicka, Jonel
Trauner, Michael
Angermayr, Bernhard
Fuhrmann, Valentin
Reiberger, Thomas
Peck-Radosavljevic, Markus
Source :
Journal of Hepatology. Jun2014, Vol. 60 Issue 6, p1135-1142. 8p.
Publication Year :
2014

Abstract

Background & Aims: Development of the portal-hypertensive syndrome is mediated by splanchnic inflammation and neoangiogenesis. Since peroxisome proliferator-activated receptor gamma (PPARγ) agonists like pioglitazone (PIO) regulate inflammatory response and inhibit angiogenesis in endothelial cells, we evaluated PIO as treatment for experimental portal hypertension. Methods: PIO (10mg/kg) or vehicle (VEH) was administered from day 21–28 after bile duct ligation (BDL), from day 0–7 after partial portal vein ligation (PPVL) or sham-operation (SO), respectively. After treatment, systemic hemodynamics, splanchnic blood flow (SMABF), portal pressure (PP), and portosystemic shunting (PSS) were assessed. Splanchnic and hepatic tissues were analyzed for angiogenic and inflammatory markers. Results: BDL and PPVL showed significantly increased PP, SMABF, and PSS compared to SO-VEH rats. While PIO treatment did not decrease PP or SMABF, PSS was significantly reduced both in cirrhotic (BDL-VEH: 71% to BDL-PIO: 41%; p <0.001) and non-cirrhotic (PPVL-VEH: 62% to PPVL-PIO: 40%; p =0.041) rats. PIO (10μM, in vitro) inhibited endothelial cell migration and significantly increased PPARγ activity in vivo. In BDL rats, PIO decreased hepatic mRNA levels of PPARγ (p =0.01) and PlGF (p =0.071), and splanchnic mRNA expression of PPARγ (p =0.017), PDGFβ (p =0.053) and TNFα (p =0.075). Accordingly, splanchnic protein expression of PPARγ (p =0.032), VEGFR2 (p =0.035), CD31 (p =0.060) and PDGFβ (p =0.066) were lower in BDL-PIO vs. BDL-VEH animals. In PPVL rats, PIO treatment decreased splanchnic gene expression of Ang2 (−12.4 fold), eNOS (−9.3 fold), PDGF (−7.0 fold), PlGF (−11.9 fold), TGFb (−8.3 fold), VEGF-A (−11.3 fold), VEGFR1 (−5.9 fold), IL1b (−14.4 fold), and IL6 (−9.6 fold). Conclusions: Pioglitazone treatment decreases portosystemic shunting via modulation of splanchnic inflammation and neoangiogenesis. Pioglitazone should be assessed for potential beneficial effects in patients with portosystemic collaterals due to portal hypertension. [Copyright &y& Elsevier]

Details

Language :
English
ISSN :
01688278
Volume :
60
Issue :
6
Database :
Academic Search Index
Journal :
Journal of Hepatology
Publication Type :
Academic Journal
Accession number :
96020410
Full Text :
https://doi.org/10.1016/j.jhep.2014.01.025