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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2015; 21(32): 9466-9475
Published online Aug 28, 2015. doi: 10.3748/wjg.v21.i32.9466
Asymmetric dimethylarginine as a mediator of vascular dysfunction in cirrhosis
Paloma Lluch, Gloria Segarra, Pascual Medina
Paloma Lluch, Department of Gastroenterology and Hepatology and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, 46010 Valencia, Spain
Gloria Segarra, Pascual Medina, Department of Physiology, University of Valencia and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, 46010 Valencia, Spain
Author contributions: All authors contributed equally to this work.
Supported by University of Valencia, Instituto de Salud Carlos III, and Consellería de Sanidad, Generalitat Valenciana.
Conflict-of-interest statement: Authors reported no conflict of interests.
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: Pascual Medina, PhD, Department of Physiology, University of Valencia and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, Avenida Blasco Ibáñez 15, 46010 Valencia, Spain. pascual.medina@uv.es
Telephone: +34-96-3864983 Fax: +34-96-3864642
Received: April 22, 2015
Peer-review started: April 24, 2015
First decision: May 18, 2015
Revised: June 5, 2015
Accepted: July 18, 2015
Article in press: July 18, 2015
Published online: August 28, 2015
Processing time: 127 Days and 21.8 Hours
Abstract

Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases (DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.

Keywords: Dimethylarginine dimethylaminohydrolase; Nitric oxide; Liver diseases; Dimethylarginines; Endothelial function

Core tip: Several lines of evidence point out that the liver is an important organ clearing asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase and a mediator of elevated intrahepatic vascular tone in cirrhosis. ADMA is degraded by dimethylarginine dimethylaminohydrolases that are expressed widely in the liver. Therefore, liver dysfunction could lead to alterations in the levels of ADMA and modifies nitric oxide bioavailability. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.