Functionalized cerium oxide nanoparticles mitigate the oxidative stress and pro-inflammatory activity associated to the portal vein endothelium of cirrhotic rats

PLoS One. 2019 Jun 24;14(6):e0218716. doi: 10.1371/journal.pone.0218716. eCollection 2019.

Abstract

Background and aims: The occurrence of endothelial alterations in the liver and in the splanchnic vasculature of cirrhotic patients and experimental models of liver diseases has been demonstrated. However, the pathological role of the portal vein endothelium in this clinical context is scarcely studied and, therefore, deserves attention. In this context, we aimed to investigate whether pathological endothelial activation occurs in the portal vein of cirrhotic rats.

Methods: Cirrhosis was induced in wistar rats by CCl4 inhalation. We generated immortalized endothelial cells from the portal vein of control (CT-iPVEC) and cirrhotic rats (CH-iPVEC) by retroviral transduction of the SV40 T antigen. We assessed differential gene expression and intracellular reactive oxygen species (ROS) levels in iPVECs and in portal veins of control and cirrhotic rats. Finally, we assessed the therapeutic effectiveness of cerium oxide nanoparticles (CeO2NP) on reversing PVEC activation and macrophage polarization.

Results: CH-iPVECs overexpressed collagen-I, endothelin-1, TIMP-1, TIMP-2, IL-6 and PlGF genes. These results were consistent with the differential expression showed by whole portal veins from cirrhotic rats. In addition, CH-iPVECs showed a significant increase in intracellular ROS and the capacity of potentiating M1 polarization in macrophages. The treatment of CH-iPVECs with CeO2NPs blocked intracellular ROS formation and IL-6 and TIMP-2 gene overexpression. In agreement with the in vitro results, the chronic treatment of cirrhotic rats with CeO2NPs also resulted in the blockade of both ROS formation and IL-6 gene overexpression in whole portal veins.

Conclusions: Endothelial cells from portal vein of cirrhotic rats depicted an abnormal phenotype characterized by a differential gene expression and the induction of M1 polarization in macrophages. We identified the excess of intracellular reactive oxygen species (ROS) as a major contributor to this altered phenotype. In addition, we demonstrated the utility of the nanomaterial cerium oxide as an effective antioxidant capable of reverse some of these pathological features associated with the portal vein in the cirrhosis condition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / administration & dosage
  • Cerium / administration & dosage*
  • Down-Regulation
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / therapy
  • Interleukin-6 / genetics
  • Liver Cirrhosis, Experimental / metabolism
  • Liver Cirrhosis, Experimental / pathology
  • Liver Cirrhosis, Experimental / therapy*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Metal Nanoparticles / administration & dosage*
  • Oxidative Stress / drug effects
  • Portal Vein / drug effects
  • Portal Vein / metabolism
  • Portal Vein / pathology
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Transcriptome

Substances

  • Antioxidants
  • Il6 protein, rat
  • Interleukin-6
  • Reactive Oxygen Species
  • Cerium
  • ceric oxide

Grants and funding

Supported by grants from the Ministerio de Economía y Competitividad (SAF 2015-64126-R to WJ, PI15-00077 to GC and SAF2016-75358-R to MM-R), co-financed by FEDER, European Union, a way of making Europe, Fundació La Marató de TV3 (Marató 120930), Spanish MINECO (MAT2015-70725-R) and the Catalan Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR-143 to VP and 2016-BP-00301 to EC). JR-V is the recipient of a BIOTRACK Postdoctoral Fellowship supported by the European Community’s Seventh Framework Programme and the MINECO (Contract 229673). CIBERehd is financed by the Instituto de Salud Carlos III. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.