The impact of sitagliptin, inhibitor of dipeptidyl peptidase-4 (DPP-4), on the ADMA-DDAH-NO pathway in ischemic and reperfused rat livers

Abstract

Background. A correlation between the level of asymmetric dimethylarginine (ADMA)-the inhibitor of the nitric oxide (NO) synthesis-and the liver function and survival after a liver transplantation has been reported. Objectives. The aim of this study was to evaluate the effect of sitagliptin-the inhibitor of dipeptidyl peptidase-4 (DPP-4)-on the NO-ADMA-dimethylarginine dimethylaminohydrolase (DDAH) pathway in rat livers subjected to ischemia/reperfusion (IR). Material and methods. The rats received sitagliptin (5 mg/kg, per os-p.o.) (groups: Slivers not subjected to IR procedure, and SIR-livers subjected to IR procedure) or a saline solution (groups: C-livers not subjected to IR procedure, and CIR-livers subjected to IR procedure) for 14 days; following this, livers in the SIR and CIR groups were subjected to ischemia (60 min) and reperfusion (24 h). Aminotransferases were measured before the surgery; additionally, the arginine (ARG), ADMA and symmetric dimethylarginine (SDMA) levels were estimated just before ischemia and during reperfusion (at 0.5 h, 4 h and 24 h). After IR, citrulline, the DDAH activity, mRNA for type 1 DDAH (DDAH1), and arginine methyltransferase type 1 (PRMT1) were determined. Results. The increase in the initial level of ARG/ADMA0 (A/A) ratio in group S compared to group C verged on statistical significance. At 0.5 h and 4 h of reperfusion, the highest concentration of ADMA was found in group CIR. At those time points, the ARG level and the A/A ratio were decreased in groups CIR and SIR as compared to groups C and S, respectively. The alanine transaminase (ALT) activity was lower in the sitagliptintreated group than in the non-treated one. The DDAH and citrulline levels were reduced in group CIR as compared to group C, but were greater in group SIR as compared to group S. The PRMT1 mRNA expression was higher in groups CIR and SIR, compared to groups C and S, respectively. Conclusions. The increased A/A ratio suggests a protective effect of sitagliptin on livers not subjected to IR. Changes in the DDAH activity and the PRMT1 mRNA expression also imply the protective activity of sitagliptin during IR.

Blueberry anthocyanin‑enriched extract ameliorates transverse aortic constriction‑induced myocardial dysfunction via the DDAH1/ADMA/NO signaling pathway in mice

“…In vivo and in vitro experiments have demonstrated that the ddaH1/adMa/no signaling pathway is closely associated with cardiovascular disease (10,12), cancer (13,36), liver diseases (37), preeclampsia (38,39) and ischemic and reperfusion injury (40). The present study demonstrated that TAC-induced a significant increase in ADMA concentration and a decrease in ddaH1 expression and no production, which were ameliorated by Bae treatment.…”

Sitagliptin Modulates Oxidative, Nitrative and Halogenative Stress and Inflammatory Response in Rat Model of Hepatic Ischemia-Reperfusion

“…Recently, a large body of evidence has accumulated showing sitagliptin effectiveness in lessening tissue damage during intestinal [ 24 , 32 ], cardiac [ 23 , 33 ], cerebral [ 30 ], testicular [ 31 ] and renal [ 28 , 29 ] ischemia-reperfusion insult. Likewise, sitagliptin has reduced the histopathological signs of injury and decreased the serum activities of ALT and AST in animal models of hepatic IR [ 21 , 22 , 25 , 26 ], acting via mechanisms employing its anti-inflammatory and antioxidative properties. Accordingly, an alleviation of oxidative stress in the ischemic liver has previously been shown, manifested by upregulated activity and/or the expression of enzymatic antioxidants, including paraoxonase-1 [ 22 ], superoxide dismutase (SOD) [ 22 , 25 ] and heme oxygenase [ 25 ], which has been accompanied by an increased concentration of reduced glutathione [ 25 ] and a diminished level of lipid peroxidation [ 22 , 25 , 26 ].…”

“…This is partly in line with our previous observations regarding the effect of this drug on selected parameters of the NO-ADMA-DDAH pathway. The 14-day treatment with sitagliptin resulted in an increase in the L-arginine/ADMA ratio in the non-ischemic group and an increase in the activity of dimethylarginine dimethylaminohydrolase (DDAH) in the ischemic group [ 21 ]. The l -Arginine/ADMA ratio reflects l -arginine bioavailability for NOS, while DDAH is an enzyme metabolizing ADMA, the main NOS inhibitor [ 67 ].…”

“…This is a follow-up study conducted on biobanked biological material collected during the original experiment [ 21 , 22 ]. Its design as well as the analytical methods used for the purpose of the current study are detailed below.…”

“…Several experimental studies have demonstrated pleiotropic properties, including the antioxidative, anti-inflammatory and antiapoptotic action of sitagliptin [ 18 , 19 ], a well-tolerated DPP-4 inhibitor with moderate side effects [ 20 ]. Accordingly, we [ 21 , 22 ], as well as others [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ], have shown that sitagliptin alleviates injury caused by IR procedure. However, the molecular background has not been fully elucidated.…”