Influence of ezetimibe on ADMA-DDAH-NO pathway in rat liver subjected to partial ischemia followed by global reperfusion

Trocha, Małgorzata; Merwid-Ląd, Anna; Sozański, Tomasz; Chlebda-Sieragowska, Ewa; Szuba, Andrzej; Dzięgiel, Piotr; Pieśniewska, Małgorzata; Fereniec-Gołębiewska, Lidia; Kwiatkowska, J; Gomułkiewicz, Agnieszka; Cwynar-Zając, Łucja; Brykner, Renata; Szeląg, Adam

doi:10.1016/s1734-1140(13)70970-8

Cited by 9 publications

(7 citation statements)

References 44 publications

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“…Serum Arg/ADMA and Arg/SDMA ratios decrease after I/R injury (table ). Arg/ADMA results obtained in serum of sham animal are comparable with those previously reported as is the marked Arg/ADMA decrease observed during reperfusion .…”

Section: Resultssupporting

confidence: 91%

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

Ferrigno

Pasqua

Berardo

et al. 2016

Basic Clin Pharma Tox

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Arginine (Arg) can be methylated to form symmetrical dimethylarginine (SDMA) and asymmetrical dimethylarginine (ADMA), the latter an endogenous inhibitor of nitric oxide synthase (NOS). SDMA is excreted in the urine, while ADMA is mainly subjected to degradation in the liver. Arg competes with ADMA and SDMA for cellular transport across cationic aminoacid transporters (CATs). We evaluated the changes in serum, tissue and biliary levels of Arg, citrulline (Cit), ADMA and SDMA and the modifications in CATs after ischaemia-reperfusion (I/R). Male Wistar rats were subjected to 30-min. partial-hepatic ischaemia or sham-operated. After 60-min. reperfusion, the concentrations of ADMA, SDMA, Arg and Cit in serum, tissue and bile were measured. Serum levels of AST, ALT and alkaline phosphatase (AP) levels were determined. mRNA of cationic transporter 2A (CAT-2A) and 2B (CAT-2B) were also quantified. An increase in ADMA and a decrease in SDMA were observed in bile at the end of reperfusion. On the contrary, lower tissue ADMA levels and higher SDMA levels were quantified. No serum changes in ADMA and SDMA were found. A decrease in Arg and an increase of Cit were detected in serum, bile and tissue after I/R. A marked increase in AST, ALT and AP levels in serum confirmed I/R injury. A decrease in mRNA transporter CAT-2A but not in CAT-2B was detected. This study supported a biliary CAT-2B-dependent transport of ADMA and demonstrated, for the first time, that the liver is also responsible for the biliary excretion of SDMA into the bile.

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Section: Resultssupporting

confidence: 91%

“…The ADMA and SDMA levels detected in plasma confirmed data previously reported in rats . No serum changes in ADMA and SDMA were found after 30‐min.…”

Section: Resultssupporting

confidence: 90%

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

Ferrigno

Pasqua

Berardo

et al. 2016

Basic Clin Pharma Tox

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“…22,23 As reported by other researchers, and in accordance with our previous experiments, in both ischemic groups, the ARG level and the A/A ratio decreased during reperfusion. [24][25][26] Asymmetric dimethylarginine is metabolized to citrulline and dimethylamine in a reaction catalyzed by DDAH. 4 Therefore, the reduced DDAH activity in the untreated group subjected to IR may be at least partially responsible for increased ADMA levels in our experiment.…”

Section: Groupsmentioning

confidence: 99%

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

Trocha¹,

Nowak²,

Merwid-Ląd³

et al. 2018

Adv Clin Exp Med

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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.

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“…During I/R injury, the main role of degradation of ADMA is conducted by DDAH-1, and the role of DDAH-2 is not so clear. It is known that renin-angiotensin-aldosterone system (RAAS) may promote the progression of I/R injury, especially in the kidney [44]. Furthermore, angiotensin type 1 receptor activation in kidneys reduces the expression of DDAH-1, but increases the expression of DDAH-2.…”

Section: Discussionmentioning

confidence: 99%

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

Ferrigno

Rizzo

Bianchi

et al. 2014

BioMed Research International

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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.

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Influence of ezetimibe on ADMA-DDAH-NO pathway in rat liver subjected to partial ischemia followed by global reperfusion

Abstract: Influence of ezetimibe on ADMA/DDAH/NO pathway demonstrated in this work may suggest protective properties of this drug on rat livers injured by IR and, to a lower extent, on livers non-subjected to IR.

Cited by 9 publications

References 44 publications

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

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

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

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

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