Blockade of the trans-sulfuration pathway in acute pancreatitis due to nitration of cystathionine β-synthase

Abstract

Acute pancreatitis is an inflammatory process of the pancreatic gland that may lead to dysregulation of the trans-sulfuration pathway. The aims of this work were firstly to study the methionine cycle as well as the trans-sulfuration pathway using metabolomic and proteomic approaches identifying the causes of this dysregulation in an experimental model of acute pancreatitis; and secondly to reveal the effects of S-adenosylmethionine administration on these pathways. Acute pancreatitis was induced by cerulein in mice, and a group of animals received S-adenosylmethionine treatment. Cerulein-induced acute pancreatitis rapidly caused marked depletion of methionine, S-adenosylmethionine, 5′-methylthioadenosine, cystathionine, cysteine, and glutathione levels in pancreas, but S-adenosylhomocysteine and homocysteine remained unchanged. Protein steady-state levels of S-adenosylhomocysteine-hydrolase and cystathionine gamma-lyase diminished but methylthioadenosine phosphorylase levels increased in pancreas with acute pancreatitis. Although cystathionine β-synthase protein levels did not change with acute pancreatitis, Nos2 mRNA and protein levels were markedly up-regulated and caused tyrosine nitration of cystathionine β-synthase in pancreas. S-adenosylmethionine administration enhanced Nos2 mRNA expression and cystathionine β-synthase nitration and triggered homocysteine accumulation in acute pancreatitis. Furthermore, S-adenosylmethionine administration promoted enrichment of the euchromatin marker H3K4me3 in the promoters of Tnf-α, Il-6, and Nos2 and enhanced the mRNA up-regulation of these genes. Accordingly, S-adenosylmethionine administration increased inflammatory infiltrate and edema in pancreas with acute pancreatitis. In conclusion, tyrosine-nitration of cystathionine β-synthase blockades the trans-sulfuration pathway in acute pancreatitis promoting homocysteine accumulation upon S-adenosylmethionine treatment.

Impairment of PGC-1 Alpha Up-Regulation Enhances Nitrosative Stress in the Liver during Acute Pancreatitis in Obese Mice

“…The present results confirm the presence of nitrosative stress in the pancreas during AP in accordance with augmented pancreatic Nos2 expression levels [8,9]. Nevertheless, we did not note any increase in the protein nitration levels in the liver after inducing pancreatitis, which is consistent with the PGC-1α-dependent repression of Nos2 in this tissue.…”

“…Oxidative stress amplifies the inflammatory process that leads to oxidative damage and contributes to the progression of extrapancreatic complications [ 5 , 6 ]. Nitrosative stress is a well-known feature of AP, with inducible nitric oxide synthase (NOS2) being the main source of nitric oxide (NO) in the pancreas during the course of this pathology [ 7 , 8 , 9 , 10 ]. In fact, Nos2 -deficient mice exhibit a low degree of pancreatic inflammation and tissue damage in the pancreas with AP [ 10 ].…”

Redox-related biomarkers in human cardiovascular disease - classical footprints and beyond

“…Determination of the GSH/GSSG ratio is the simplest readout of the cellular or serum/plasma redox state, however, with only limited prognostic implications [ 43 ]. Assessment of the trans-sulfuration pathway may be a more meaningful approach in the future [ 207 ]. Redox lipidomics (or oxidative phospholipidomics) [ 208 , 209 ] and phosphoproteomics [ 210 ] represent smaller subsets of the metabolome and proteome that are optimized to assess altered redox processes or oxidative stress conditions.…”

Vitamin B12 Attenuates Acute Pancreatitis by Suppressing Oxidative Stress and Improving Mitochondria Dysfunction via CBS/SIRT1 Pathway

“…Vitamin B 12 (VB 12), also known as cobalamin, is an essential cofactor in humans that we obtain from our diet [ 11 ]. Failure of VB 12 supply leads to inadequate synthesis of S-Adenosylmethionine (SAM), an allosteric activator of CBS, which is difficult to maintain the activity of CBS [ 12 , 13 ]. Existing research demonstrated that VB 12 administration significantly blunts the kidney damage caused by ischemia/reperfusion via marked suppression of ROS and associated inflammation and apoptotic cell death [ 14 ].…”