Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 14, 2015; 21(14): 4126-4135
Published online Apr 14, 2015. doi: 10.3748/wjg.v21.i14.4126
Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure
Nicholas G Theodorakis, Yining N Wang, Vyacheslav A Korshunov, Mary A Maluccio, Nicholas J Skill
Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States
Yining N Wang, Vyacheslav A Korshunov, School of Medicine, University of Rochester, Rochester, NY 14611, United States
Author contributions: Theodorakis NG, Wang YN, Korshunov VA and Skill NJ performed the research; Skill NJ and Theodorakis NG designed the research; Skill NJ and Maluccio MA wrote the paper.
Supported by The Departments of Surgery at the University of Rochester and Indiana University.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Nicholas J Skill, PhD, Assistant Professor, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, C519, 980 West Walnut Street (R3), Indianapolis, IN 46202, United States. nskill@iupui.edu
Telephone: +1-317-2744532 Fax: +1-317-2748046
Received: June 12, 2014
Peer-review started: June 12, 2014
First decision: July 9, 2014
Revised: July 30, 2014
Accepted: October 15, 2014
Article in press: October 15, 2014
Published online: April 14, 2015
Abstract

AIM: Portal hypertension is a common complication of liver cirrhosis and significantly increases mortality and morbidity. Previous reports have suggested that the compound thalidomide attenuates portal hypertension (PHT). However, the mechanism for this action is not fully elucidated. One hypothesis is that thalidomide destabilizes tumor necrosis factor α (TNFα) mRNA and therefore diminishes TNFα induction of nitric oxide synthase (NOS) and the production of nitric oxide (NO). To examine this hypothesis, we utilized the murine partial portal vein ligation (PVL) PHT model in combination with endothelial or inducible NOS isoform gene knockout mice.

METHODS: Wild type, inducible nitric oxide synthase (iNOS)-/- and endothelial nitric oxide synthase (eNOS)-/- mice received either PVL or sham surgery and were given either thalidomide or vehicle. Serum nitrate (total nitrate, NOx) was measured daily for 7 d as a surrogate of NO synthesis. Serum TNFα level was quantified by enzyme-linked immunosorbent assay. TNFα mRNA was quantified in liver and aorta tissue by reverse transcription-polymerase chain reaction. PHT was determined by recording splenic pulp pressure (SPP) and abdominal aortic flow after 0-7 d. Response to thalidomide was determined by measurement of SPP and mean arterial pressure (MAP).

RESULTS: SPP, abdominal aortic flow (Qao) and plasma NOx were increased in wild type and iNOS-/- PVL mice when compared to sham operated control mice. In contrast, SPP, Qao and plasma NOx were not increased in eNOS-/- PVL mice when compared to sham controls. Serum TNFα level in both sham and PVL mice was below the detection limit of the commercial ELISA used. Therefore, the effect of thalidomide on serum TNFα levels was undetermined in wild type, eNOS-/- or iNOS-/- mice. Thalidomide acutely increased plasma NOx in wild type and eNOS-/- mice but not iNOS-/- mice. Moreover, thalidomide temporarily (0-90 min) decreased mean arterial pressure, SPP and Qao in wild type, eNOS-/- and iNOS-/- PVL mice, after which time levels returned to the respective baseline.

CONCLUSION: Thalidomide does not reduce portal pressure in the murine PVL model by modulation of NO biosynthesis. Rather, thalidomide reduces PHT by decreasing MAP by an undetermined mechanism.

Keywords: Portal hypertension, Thalidomide, Nitric oxide, Knockout mice, Endothelial nitric oxide synthase, Inducible nitric oxide synthase, Tumor necrosis factor alpha

Core tip: The research innovation detailed in this manuscript is the use of nitric oxide synthase (NOS) isoform specific gene deleted mice to better understand the underlying mechanisms for the development of portal hypertension (PHT). PHT is a significant complication of liver disease and increases morbidity and mortality. Our study examined the hypothesis that the compound thalidomide reduces PHT by decreasing the biosynthesis of nitric oxide (NO) via destabilizing tumor necrosis factor alpha mRNA levels. We demonstrate that thalidomide induces NO via increased inducible nitric oxide synthase isoform of NOS; however, thalidomide reduction in PHT was NOS isoform independent.