Probiotics (VSL#3) prevent endothelial dysfunction in rats with portal hypertension: role of the angiotensin system.

Sherzad K Rashid,Monique Oswald-Mammosser,Noureddine Idris Khodja,Valérie B Schini-Kerth,Nelly Boehm,Cyril Auger,Mahmoud Alhosin,Concepción Peiró

doi:10.1371/journal.pone.0097458

Abstract

AimsPortal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL) was evaluated.MethodsRats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt−1.day−1) for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry.ResultsBoth NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IKCa and SKCa and an increased expression of endothelial NO synthase (eNOS). In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IKCa, SKCa and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-α, IL-1α and MCP-1 levels.ConclusionsThese findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system.

Highlights

Advanced chronic liver diseases are characterized by generalized progressive vasodilatation, related to portal hypertension (PH), which is especially observed in the splanchnic and pulmonary beds
In a rat model of partial portal vein ligation, Albrades et al [1] reported that the initial event in response to PH is an up-regulation of vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculation
VSL#3 treatment prevents the chronic bile duct ligated (CBDL)-induced impaired endothelium-dependent hyperpolarization (EDH) but not nitric oxide (NO) component of the relaxation to acetylcholine in mesenteric artery rings

Summary

Introduction

Advanced chronic liver diseases are characterized by generalized progressive vasodilatation, related to portal hypertension (PH), which is especially observed in the splanchnic and pulmonary beds. Several lines of evidence support a role for an increased formation of nitric oxide (NO) in the general vasodilatation in chronic liver diseases in patients [6] and in the chronic bile duct ligated (CBDL) rat model [2,4]. Earlier studies have reported that treatment with either antiobiotics or pentoxifylline, an inhibitor of TNF-a, to prevent BT and/or its consequences improves the vasodilatation in CBDL rats [12,16] and in patients with liver cirrhosis [17,18]. The aim of the present study was to evaluate the effect of the probiotic VSL#3 formulation on the vascular dysfunction in an animal model of biliary cirrhosis with PH with a special attention to oxidative stress and the local angiotensin system

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Results

Discussion

Conclusion