Changes in ADMA/DDAH Pathway after Hepatic Ischemia/Reperfusion Injury in Rats: The Role of Bile

Abstract

We investigated the effects of hepatic ischemia/reperfusion (I/R) injury on asymmetric dimethylarginine (ADMA, a nitric oxide synthase inhibitor), protein methyltransferase (PRMT) and dimethylarginine dimethylaminohydrolase (DDAH) (involved, resp., in ADMA synthesis and degradation), and the cationic transporter (CAT). Male Wistar rats were subjected to 30 or 60 min hepatic ischemia followed by 60 min reperfusion. ADMA levels in serum and bile were determined. Tissue ADMA, DDAH activity, DDAH-1 and CAT-2 protein, DDAH-1 and PRMT-1 mRNA expression, GSH/GSSG, ROS production, and lipid peroxidation were detected. ADMA was found in bile. I/R increased serum and bile ADMA levels while an intracellular decrease was detected after 60 min ischemia. Decreased DDAH activity, mRNA, and protein expression were observed at the end of reperfusion. No significant difference was observed in GSH/GSSG, ROS, lipid peroxidation, and CAT-2; a decrease in PRMT-1 mRNA expression was found after I/R. Liver is responsible for the biliary excretion of ADMA, as documented here for the first time, and I/R injury is associated with an oxidative stress-independent alteration in DDAH activity. These data are a step forward in the understanding of the pathways that regulate serum, tissue, and biliary levels of ADMA in which DDAH enzyme plays a crucial role.

Admission levels of asymmetric and symmetric dimethylarginine predict long-term outcome in patients with community-acquired pneumonia

“…While ADMA acts as a competitive inhibitor of the NOS, SDMA is a competitor of arginine transport but does not interfere with NOS [8]. Thus, an elevated serum ADMA level results in lowered NO levels, which leads to vasoconstriction, augmented thrombocyte aggregation, and cell adhesion to the endothelium and promotes proliferation of vascular muscle cells [9]. ADMA is metabolized to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) and a small fraction is renally excreted whereas SDMA is almost entirely eliminated by the kidneys.…”

The restorative effect of ascorbic acid on liver injury inducedby asymmetric dimethylarginine

“…CAT-2B is a low-capacity transporter and demonstrates high affinity to cationic amino acids, particularly ADMA (Closs et al, 1997). The liver takes up the most amounts of ADMA from serum and metabolizes it, mediated by particularly DDAH1 (Ferrigno et al, 2014). It was detected in a study by Siroen et al that patients with preoperative liver transplantation had higher levels ADMA when compared with healthy subjects.…”

“…The liver metabolizes ADMA particularly by dimethylarginine dimethylaminohydrolase 1 (DDAH1). Beside this, ADMA may also be drained through the bile duct (Ferrigno et al, 2014) and broken down to α-keto-d-(N,N-dimethylguanidino)valeric acid by alanine glyoxylate aminotransferase 2 (Vallance and Leiper, 2004;Rodionov et al, 2010).…”

“…Some changes occur in the pathway of ADMA/DDAH also in the case of hepatic ischemia/reperfusion (IR). In the early period of reperfusion (1 h), DDAH1 mRNA and protein expressions show a reduction, whereas ADMA levels increase (Ferrigno et al, 2014). Increased ADMA under conditions of IR changes the balance between NO and endothelin and thereby causes vasoconstriction, which may lead to hepatic deterioration (Laleman et al, 2005).…”

Changes in Biliary Levels of Arginine and its Methylated Derivatives after Hepatic Ischaemia/Reperfusion

“…Several experimental and clinical studies have evaluated the handling of ADMA and SDMA by the body, but their metabolic fate is not fully understood. ADMA and SDMA can be detected in plasma, urine, cerebrospinal and bronchoalveolar fluids ; we recently reported that ADMA is also secreted in bile and a time‐dependent increase of ADMA occurs during hepatic I/R injury .…”