title: Liver plays a central role in asymmetric dimethylarginine-mediated organ injury.
abstract: Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.
authors.affiliation: Andrea Ferrigno, Laura G Di Pasqua, Clarissa Berardo, Plinio Richelmi, Mariapia Vairetti, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferrigno
authors.affiliation: Andrea Ferrigno, Laura G Di Pasqua, Clarissa Berardo, Plinio Richelmi, Mariapia Vairetti, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Di Pasqua
authors.affiliation: Andrea Ferrigno, Laura G Di Pasqua, Clarissa Berardo, Plinio Richelmi, Mariapia Vairetti, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Berardo
authors.affiliation: Andrea Ferrigno, Laura G Di Pasqua, Clarissa Berardo, Plinio Richelmi, Mariapia Vairetti, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
authors.forename: Plinio
authors.initials: P
authors.lastname: Richelmi
authors.affiliation: Andrea Ferrigno, Laura G Di Pasqua, Clarissa Berardo, Plinio Richelmi, Mariapia Vairetti, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
authors.forename: Mariapia
authors.initials: M
authors.lastname: Vairetti
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D016638:Critical Illness; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009102:Multiple Organ Failure / Q000209:etiology / Q000378:metabolism; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C018524:N,N-dimethylarginine; D001120:Arginine
keywords: Asymmetric dimethylarginine; Liver; Multiple organ failure; Nitric oxide; Nitric oxide-synthase