Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats
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Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats. / 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.
in: J HEPATOL, Jahrgang 60, Nr. 6, 01.06.2014, S. 1135-42.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats
AU - Schwabl, Philipp
AU - Payer, Berit A
AU - Grahovac, Jelena
AU - Klein, Sabine
AU - Horvatits, Thomas
AU - Mitterhauser, Markus
AU - Stift, Judith
AU - Boucher, Yves
AU - Trebicka, Jonel
AU - Trauner, Michael
AU - Angermayr, Bernhard
AU - Fuhrmann, Valentin
AU - Reiberger, Thomas
AU - Peck-Radosavljevic, Markus
N1 - Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2014/6/1
Y1 - 2014/6/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.jhep.2014.01.025
DO - 10.1016/j.jhep.2014.01.025
M3 - SCORING: Journal article
C2 - 24530596
VL - 60
SP - 1135
EP - 1142
JO - J HEPATOL
JF - J HEPATOL
SN - 0168-8278
IS - 6
ER -
