Exogenous Asymmetric Dimethylarginine (ADMA) in Pathogenesis of Ischemia-Reperfusion-Induced Gastric Lesions: Interaction with Protective Nitric Oxide (NO) and Calcitonin Gene-Related Peptide (CGRP)

Marcin Magierowski,Gracjana Krzysiek-Maczka,Marcin Surmiak,Agata Ptak-Belowska,Katarzyna Jasnos,Tomasz Brzozowski,Zbigniew Sliwowski,Slawomir Kwiecien

doi:10.3390/ijms15034946

Marcin Magierowski, Gracjana Krzysiek-Maczka + Show 6 more

Open Access

https://doi.org/10.3390/ijms15034946

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Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthesis inhibitor and pro-inflammatory factor. We investigated the role of ADMA in rat gastric mucosa compromised through 30 min of gastric ischemia (I) and 3 h of reperfusion (R). These I/R animals were pretreated with ADMA with or without the combination of l-arginine, calcitonin gene-related peptide (CGRP) or a small dose of capsaicin, all of which are known to afford protection against gastric lesions, or with a farnesoid X receptor (FXR) agonist, GW 4064, to increase the metabolism of ADMA. In the second series, ADMA was administered to capsaicin-denervated rats. The area of gastric damage was measured with planimetry, gastric blood flow (GBF) was determined by H2-gas clearance, and plasma ADMA and CGRP levels were determined using ELISA and RIA. ADMA significantly increased I/R-induced gastric injury while significantly decreasing GBF, the luminal NO content, and the plasma level of CGRP. This effect of ADMA was significantly attenuated by pretreatment with CGRP, l-arginine, capsaicin, or a PGE2 analogue. In GW4064 pretreated animals, the I/R injury was significantly reduced and this effect was abolished by co-treatment with ADMA. I/R damage potentiated by ADMA was exacerbated in capsaicin-denervated animals with a further reduction of CGRP. Plasma levels of IL-10 were significantly decreased while malonylodialdehyde (MDA) and plasma TNF-α contents were significantly increased by ADMA. In conclusion, ADMA aggravates I/R-induced gastric lesions due to a decrease of GBF, which is mediated by a fall in NO and CGRP release, and the enhancement of lipid peroxidation and its pro-inflammatory properties.

Highlights

Under physiological conditions free L-arginine (L-arg) can be metabolized by arginases toL-ornithine and urea, or it can serve as a substrate for nitric oxide synthase (NOS) to synthesize nitric oxide (NO) and L-citrulline [1] the protein-incorporated L-arg residues are methylated through the action of enzymes called protein arginine methyltransferases (PRMTs) known to generateNG-monomethyl-L-arginine (L-NMMA), asymmetric dimethyl arginine (ADMA) or symmetric dimethyl arginine (SDMA)
The activation of farnesoid X receptor (FXR) with its agonist, GW4064, increased activity of Dimethylarginine dimethylaminohydrolase (DDAH)-1 and decreased plasma circulating levels of ADMA, resulting in significant protection against cisplatin-induced toxicity [16]. Since these findings provided an insight into the mechanism by which FXR may affect NO levels through modulation of blood ADMA levels via direct regulation of hepatic DDAH1 expression and activity [17], we tested the hypothesis that GW4064 could afford protection of I/R-induced gastric lesions in the absence and presence of ADMA
Our preliminary studies revealed that ADMA administered alone in a dose of 20 mg/kg (i.g.) did not induce gross damage detectable in the gastric mucosa and this effect has been omitted for the sake of clarity

Summary

Introduction

Under physiological conditions free L-arginine (L-arg) can be metabolized by arginases to. The activation of FXR with its agonist, GW4064, increased activity of DDAH-1 and decreased plasma circulating levels of ADMA, resulting in significant protection against cisplatin-induced toxicity [16]. The excessive generation of reactive oxygen species (ROS), adhesion of neutrophils to endothelial cells, the activation of various proinflammatory mediators and the alternation in gastric acid secretion have been implicated in the pathogenesis of I/R-induced gastric mucosal injury [19]. Under pathological conditions, such as damage by I/R, the superoxide (O2−) reacts with NO to produce peroxynitrite (ONOO−), one of the most powerful and highly damaging oxidants [20]. We examined the effect of a synthetic prostaglandin (PG) E2 analog, the prototype of gastroprotective substances [29,30], on I/R-induced gastric lesions and the accompanying changes in plasma anti-inflammatory (interleukin (IL)-10) and proinflammatory cytokine (TNF-α) levels with or without ADMA administration

Results and Discussion

Experimental Section

Determination of Gastric Blood Flow and the Area of Gastric Lesions

Determination of Luminal NO Release and the Gastric Mucosal MDA Content

Conclusions