Pioglitazone Decreases Portosystemic Shunting by Modulating Inflammation and Angiogenesis in Cirrhotic and Non-Cirrhotic Portal Hypertensive Rats

J Hepatol. 2014 Jun;60(6):1135-42. doi: 10.1016/j.jhep.2014.01.025. Epub 2014 Feb 13.

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 (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), 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 (10 μM, 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.

Keywords: Angiogenesis; BDL; Inflammation; PPARγ; PPVL; Pioglitazone; Portal hypertension; Portosystemic shunting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Disease Models, Animal
  • Hemodynamics / drug effects
  • Hemodynamics / physiology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypertension, Portal / drug therapy*
  • Hypertension, Portal / immunology
  • Hypertension, Portal / physiopathology
  • Hypoglycemic Agents / pharmacology
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / physiopathology
  • Liver Circulation / drug effects
  • Liver Circulation / physiology
  • Liver Cirrhosis, Experimental / drug therapy*
  • Liver Cirrhosis, Experimental / immunology
  • Liver Cirrhosis, Experimental / physiopathology
  • Male
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / immunology
  • Neovascularization, Pathologic / physiopathology
  • PPAR gamma / metabolism
  • Pioglitazone
  • Portal Pressure / drug effects*
  • Portal Pressure / physiology
  • Rats, Sprague-Dawley
  • Splanchnic Circulation / drug effects
  • Splanchnic Circulation / immunology
  • Splanchnic Circulation / physiology
  • Thiazolidinediones / pharmacology*

Substances

  • Hypoglycemic Agents
  • PPAR gamma
  • Thiazolidinediones
  • Pioglitazone