Dataset Information

Alterations of Asymmetric Dimethylarginine (ADMA)-Containing Protein Profiles Associated with Chronic Pancreatitis Pathogenesis

ABSTRACT:

Objective

The pathophysiological mechanisms of chronic pancreatitis (CP) still remain poorly understood. In this study, we aimed to characterize asymmetric dimethylarginine (ADMA)-containing proteins in pancreatic tissues and its relationship with CP pathogenesis.

Methods

Totally 36 patients with CP were enrolled in this study. Seven other cholangiocarcinoma patients without pancreas involvements or patients with benign pancreatic tumors were included as the control group. Total proteins in human pancreatic tissues were digested by trypsin, and ADMA-containing peptides were enriched via immunoaffinity purification. The LC-MS/MS was performed to characterize ADMA-containing peptides and their modification sites in CP tissues. Relative asymmetric arginine dimethylation levels of HNRNPA3 proteins in human pancreatic tissues were detected by the immunoprecipitation combined with Western blot. The serum inflammatory factors were determined via the ELISA method.

Results

A total of 134 ADMA sites in the control group and 137 ADMA sites in CP tissues were characterized by mass spectrometry, which belong to 93 and 94 ADMA-containing proteins in the control group and CP tissues, respectively. Glycine and proline residues were significantly overrepresented in the flanking sequences of ADMA sites. ADMA-containing proteins in the CP tissues were associated with various biological processes, especially the RNA metabolism and splicing pathways. Multiple protein members of the spliceosome pathway such as HNRNPA3 possess ADMA sites in the CP tissues. HNRNPA3 dimethylation levels were greatly increased in CP tissues, which were positively correlated with inflammatory factors.

Conclusion

The pathogenesis of CP is associated with alterations of asymmetric arginine dimethylation in pancreatic tissues.

SUBMITTER: Tan C

PROVIDER: S-EPMC8714020 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Asymmetric protein-arginine dimethylation is a major post-translational modification (PTM) catalyzed by protein-arginine methyltransferase (PRMT). Regular proteolysis releases asymmetric dimethylarginine (ADMA). Of the daily produced ADMA, about 10% are excreted unchanged in the urine. The remaining 90% are hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and dimethylamine (DMA), which is readily excreted in the urine. The PRMT/DDAH pathway is almost the exclusive origin of urinary ADMA and the major source of urinary DMA. Dietary fish and seafood represent additional abundant sources of urinary DMA. The present article provides an overview of urinary ADMA and DMA reported thus far in epidemiological, clinical and pharmacological studies, in connection with the L-arginine/nitric oxide (NO) pathway and beyond, in neonates, children and adolescents, young and elderly subjects, males and females. Discussed diseases mainly include those relating to the renal and cardiovascular systems such as peripheral arterial occlusive disease, coronary artery disease, chronic kidney disease, rheumatoid arthritis, Becker muscular disease, Duchenne muscular disease (DMD), attention deficit hyperactivity disorder (ADHD), and type I diabetes. Under standardized conditions involving the abstinence of DMA-rich fresh and canned fish and seafood, urinary DMA and ADMA are useful as measures of whole-body asymmetric arginine-dimethylation in health and disease. The creatinine-corrected excretion rates of DMA range from 10 to 80 µmol/mmol in adults and up to 400 µmol/mmol in children and adolescents. The creatinine-corrected excretion rates of ADMA are on average 10 times lower. In general, diseases are associated with higher urinary DMA and ADMA excretion rates, and pharmacological treatment, such as with steroids and creatine (in DMD), decreases their excretion rates, which may be accompanied by a decreased urinary excretion of nitrate, the major metabolite of NO. In healthy subjects and in rheumatoid arthritis patients, the urinary excretion rate of DMA correlates positively with the excretion rate of dihydroxyphenylglycol (DHPG), the major urinary catecholamines metabolite, suggesting a potential interplay in the PRMT/DDAH/NO pathway.