Research Article
Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats Philipp Schwabl1,2, , Berit A. Payer1,2, , Jelena Grahovac3, Sabine Klein4, Thomas Horvatits1, Markus Mitterhauser5, Judith Stift6, Yves Boucher3, Jonel Trebicka4, Michael Trauner1, Bernhard Angermayr1,2, Valentin Fuhrmann1, Thomas Reiberger1,2,3, Markus Peck-Radosavljevic1,2,⇑ 1
Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria; 2Vienna Hepatic Hemodynamic Lab, Vienna, Austria; 3Edwin L. Steele Laboratory of Tumor Biology, Dept. of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 4Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine I, University of Bonn, Germany; 5 Dept. of Nuclear Medicine, Medical University Vienna, Austria; 6Dept. of Pathology, Medical University Vienna, Austria
Background & Aims: Development of the portal-hypertensive syndrome is mediated by splanchnic inflammation and neoangiogenesis. Since peroxisome proliferator-activated receptor gamma (PPARc) agonists like pioglitazone (PIO) regulate inflammatory response and inhibit angiogenesis in endothelial cells, we evaluated PIO as treatment for experimental portal hypertension. Methods: PIO (10 mg/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), respec-
Keywords: Angiogenesis; Inflammation; Portal hypertension; BDL; PPVL; Pioglitazone; Portosystemic shunting; PPARc. Received 16 April 2013; received in revised form 20 January 2014; accepted 22 January 2014; available online 13 February 2014 ⇑ Corresponding author. Address: Div. of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +43 1404006589; fax: +43 1404004735. E-mail address: [email protected] (M. Peck-Radosavljevic). These authors contributed equally to this work. Abbreviations: PPARc, Peroxisome proliferator-activated receptor gamma; PIO, Pioglitazone; VEH, Vehicle; BDL, Bile duct ligation; PPVL, Partial portal vein ligation; SO, Sham-operation; SMABF, Splanchnic blood flow; PP, Portal pressure; PSS, Portosystemic shunting; PIGF, Placental growth factor; PDGFb, Platelet-derived growth factor beta; TNFa, Tumor necrosis factor alpha; VEGFR2, Vascular endothelial growth factor receptor 2; CD31, Pecam1, Platelet endothelial cell adhesion molecule; Ang2, Angiopoietin-2; eNOS, Nos3, Endothelial nitric oxide synthetase; TGFb1, TGFb, Transforming growth factor beta1; VEGFa, Vascular endothelial growth factor a; VEGFR1, Flt1, Vascular endothelial growth factor receptor 1; IL1b, Interleukin 1b; IL6, Interleukin 6; PHT, Portal hypertension; PSCs, Portosystemic collaterals; NASH, Non-alcoholic steatohepatitis; MAP, Mean arterial pressure; HR, Heart rate; SMAR, Superior mesenteric artery resistance; PPRE, Peroxisome proliferator response element; HUVECs, Human umbilical vein endothelial cells; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DMSO, Dimethylsulfoxide; Mmp9, Matrix metalloprotease 9; TGFa, Transforming growth factor alpha; CCl2, Chemokine C-C motif ligand 2; CCR1, C-C chemokine receptor type 1; CXCl2, Chemokine C-X-C motif ligand 2; TNFsf11 = RANKL, Tumor necrosis factor ligand superfamily member 11; IL3, Interleukin 3; IL5, Interleukin 5; MIF, Macrophage migration inhibitory factor; aSMA, Alpha smooth muscle actin.
tively. 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
Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats Philipp Schwabl1,2, , Berit A. Payer1,2, , Jelena Grahovac3, Sabine Klein4, Thomas Horvatits1, Markus Mitterhauser5, Judith Stift6, Yves Boucher3, Jonel Trebicka4, Michael Trauner1, Bernhard Angermayr1,2, Valentin Fuhrmann1, Thomas Reiberger1,2,3, Markus Peck-Radosavljevic1,2,⇑ 1
Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria; 2Vienna Hepatic Hemodynamic Lab, Vienna, Austria; 3Edwin L. Steele Laboratory of Tumor Biology, Dept. of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 4Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine I, University of Bonn, Germany; 5 Dept. of Nuclear Medicine, Medical University Vienna, Austria; 6Dept. of Pathology, Medical University Vienna, Austria
Background & Aims: Development of the portal-hypertensive syndrome is mediated by splanchnic inflammation and neoangiogenesis. Since peroxisome proliferator-activated receptor gamma (PPARc) agonists like pioglitazone (PIO) regulate inflammatory response and inhibit angiogenesis in endothelial cells, we evaluated PIO as treatment for experimental portal hypertension. Methods: PIO (10 mg/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), respec-
Keywords: Angiogenesis; Inflammation; Portal hypertension; BDL; PPVL; Pioglitazone; Portosystemic shunting; PPARc. Received 16 April 2013; received in revised form 20 January 2014; accepted 22 January 2014; available online 13 February 2014 ⇑ Corresponding author. Address: Div. of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +43 1404006589; fax: +43 1404004735. E-mail address: [email protected] (M. Peck-Radosavljevic). These authors contributed equally to this work. Abbreviations: PPARc, Peroxisome proliferator-activated receptor gamma; PIO, Pioglitazone; VEH, Vehicle; BDL, Bile duct ligation; PPVL, Partial portal vein ligation; SO, Sham-operation; SMABF, Splanchnic blood flow; PP, Portal pressure; PSS, Portosystemic shunting; PIGF, Placental growth factor; PDGFb, Platelet-derived growth factor beta; TNFa, Tumor necrosis factor alpha; VEGFR2, Vascular endothelial growth factor receptor 2; CD31, Pecam1, Platelet endothelial cell adhesion molecule; Ang2, Angiopoietin-2; eNOS, Nos3, Endothelial nitric oxide synthetase; TGFb1, TGFb, Transforming growth factor beta1; VEGFa, Vascular endothelial growth factor a; VEGFR1, Flt1, Vascular endothelial growth factor receptor 1; IL1b, Interleukin 1b; IL6, Interleukin 6; PHT, Portal hypertension; PSCs, Portosystemic collaterals; NASH, Non-alcoholic steatohepatitis; MAP, Mean arterial pressure; HR, Heart rate; SMAR, Superior mesenteric artery resistance; PPRE, Peroxisome proliferator response element; HUVECs, Human umbilical vein endothelial cells; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DMSO, Dimethylsulfoxide; Mmp9, Matrix metalloprotease 9; TGFa, Transforming growth factor alpha; CCl2, Chemokine C-C motif ligand 2; CCR1, C-C chemokine receptor type 1; CXCl2, Chemokine C-X-C motif ligand 2; TNFsf11 = RANKL, Tumor necrosis factor ligand superfamily member 11; IL3, Interleukin 3; IL5, Interleukin 5; MIF, Macrophage migration inhibitory factor; aSMA, Alpha smooth muscle actin.
tively. 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
