Involvement of the HIF-1α and Wnt/β-catenin pathways in the protective effects of losartan on fatty liver graft with ischaemia/reperfusion injury

2013 ◽  
Vol 126 (2) ◽  
pp. 163-174 ◽  
Author(s):  
Ying-Ying Yang ◽  
Pei-Chang Lee ◽  
Yi-Tsau Huang ◽  
Wei-Ping Lee ◽  
Ying-Ju Kuo ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Elevated Serum ◽  
Liver Graft ◽  
Signalling Pathways ◽  
Protective Agent ◽  
Ischaemia Reperfusion Injury ◽  
Positive Effects ◽  
Ischaemia Reperfusion ◽  
Hepatic Congestion ◽  
Pre Treatment

Besides cardioprotective effects, the AT1R (angiotensin-II type 1 receptor) antagonist losartan protects the liver from IRI [IR (ischaemia/reperfusion) injury], but the mechanism has not been fully determined. The HIF (hypoxia inducible factor)-1α and Wnt/β-catenin signalling pathways have been reported to be involved in the mechanism of liver IRI. Therefore the aim of the present study was to determine whether the Wnt/HIF axis is part of the mechanism of the positive effect of AngII inhibition by losartan in liver IRI in rats. Various measurements were made in MCD/HF-NASH (methionine- and choline-deficient-diet/high-fat-diet-induced non-alcoholic steatohepatitis) rats with liver IRI. Acute losartan pre-administration markedly reversed the IR-suppressed levels of the hepatic-protective factors IL (interleukin)-6, IFN (interferon)-γ, Wnt3a, β-catenin and HIF-1α, and decreased hepatic blood flow and IR-elevated serum ALT (alanine aminotransferase), hepatic TNF (tumour necrosis factor)-α, IL-1α, hepatic congestion, vacuolization and necrosis, hepatic Suzuki IRI scores, necrotic index and levels of TBARS (thiobarbituric acid-reacting substances) in MCD/HF-NASH rats. Furthermore, acute Wnt3a pre-treatment significantly inhibited IR-elevated serum ALT, hepatic Suzuki IRI scores and TBARS, and restored the IR-depleted β-catenin/HIF-1α activity in MCD/HF-NASH rats. Simultaneous acute sFRP2 (secreted frizzled-related protein 2; a Wnt3a inhibitor) pre-treatment eliminated the losartan-related beneficial effects in MCD/HF-NASH rats with liver IRI, which was accompanied by a decrease in hepatic HIF-1α/β-catenin activity. Losartan-induced up-regulation of HIF-1α and Wnt/β-catenin signalling was associated with the recovery of IR-inhibited hepatic Bcl-2, Mn-SOD (manganese superoxide), Cu/Zn-SOD (copper/zinc superoxide) and GSH levels, and the suppression of IR-increased hepatic catalase and caspase 3/caspase 8 levels in MCD/HF-NASH rats. In conclusion, up-regulation of the HIF-1α and Wnt/β-catenin signalling pathways are part of the mechanism of the positive effects of losartan-related AngII inhibition in MCD/HF-NASH rats with liver IRI. Our study highlights the potential of the dual-organ protective agent losartan in NASH patients with steatotic livers and cardiovascular risk.

Enteral donor pre-treatment with ursodeoxycholic acid protects the liver against ischaemia-reperfusion injury in rats

2005 ◽  
Author(s):  
Grzegorz Nowak ◽  
Ulf G. Nor�n ◽  
Annika Wernerson ◽  
Hanns-Ulrich Marschall ◽  
Lennart M�ller ◽  
...  
Keyword(s):  
Ursodeoxycholic Acid ◽  
Reperfusion Injury ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Pre Treatment

Enteral donor pre-treatment with ursodeoxycholic acid protects the liver against ischaemia-reperfusion injury in rats

2004 ◽  
Vol 17 (12) ◽  
pp. 804-809 ◽  
Author(s):  
Grzegorz Nowak ◽  
Ulf G. Noren ◽  
Annika Wernerson ◽  
Hanns-Ulrich Marschall ◽  
Lennart Moller ◽  
...  
Keyword(s):  
Ursodeoxycholic Acid ◽  
Reperfusion Injury ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Pre Treatment

scholarly journals Tripartite Motif 8 Deficiency Relieves Hepatic Ischaemia/reperfusion Injury via TAK1-dependent Signalling Pathways

2019 ◽  
Vol 15 (8) ◽  
pp. 1618-1629 ◽  
Author(s):  
Qiu Tao ◽  
Wang Tianyu ◽  
Zhou Jiangqiao ◽  
Chen Zhongbao ◽  
Ma Xiaoxiong ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Signalling Pathways ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Tripartite Motif

scholarly journals Protective Antioxidant Effects of Carvedilol in a Rat Model of Ischaemia-reperfusion Injury

2005 ◽  
Vol 33 (5) ◽  
pp. 528-536 ◽  
Author(s):  
H Akbas ◽  
M Ozden ◽  
M Kanko ◽  
H Maral ◽  
S Bulbul ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Rat Model ◽  
Control Treatment ◽  
Control Group ◽  
Protective Effects ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Reperfusion Period ◽  
Pre Treatment ◽  
Group 2

This study investigated the protective effects of carvedilol, a potent antioxidant, in a rat model of tourniquet-induced ischaemia-reperfusion injury of the hind limb. Thirty rats were divided equally into three groups: the control group (group 1) was only anaesthetized, without creating an ischaemia-reperfusion injury; group 2 was submitted to ischaemia (4 h), followed by a 2-h reperfusion period; and group 3 was pre-treated with carvedilol (2 mg/kg per day) for 10 days prior to ischaemia-reperfusion. Ischaemia-reperfusion produced a significant decrease in superoxide dismutase and glutathione peroxidase activities in the liver, lungs, muscle and serum compared with control treatment, and pre-treatment with carvedilol prevented these changes. Ischaemia-reperfusion caused a significant increase in malondialdehyde and nitric oxide (NO) levels in liver, lungs, muscle (except NO) and serum compared with control treatment, and carvedilol prevented these changes. In conclusion, it might be inferred that carvedilol could be used safely to prevent oxidative injury during reperfusion following ischaemia in humans.

Protective agents used as additives in University of Wisconsin solution to promote protection against ischaemia–reperfusion injury in rat lung

1998 ◽  
Vol 95 (3) ◽  
pp. 369-376
Author(s):  
Chi-Huei CHIANG ◽  
Kerry WU ◽  
Cheng-Ping YU ◽  
Wann-Cherng PERNG ◽  
Horng-Chin YAN ◽  
...  
Keyword(s):  
Weight Gain ◽  
Lung Injury ◽  
Reperfusion Injury ◽  
Protective Agent ◽  
Ischaemia Reperfusion Injury ◽  
Lung Weight ◽  
Protective Agents ◽  
University Of Wisconsin ◽  
Ischaemia Reperfusion ◽  
Wisconsin Solution

1.An intervention to reduce ischaemia–reperfusion lung injury will be an important advance in transplant medicine. Although the mechanisms associated with producing ischaemia–reperfusion endothelial injury have not been completely elucidated, many of the injury mediators have been studied in detail. While no single pharmacological therapy is likely to be totally effective in eliminating this complex injury, we have developed a mixture of agents that are known to block pathways involved in producing ischaemia–reperfusion-associated lung vascular injury. 2.The present study modified University of Wisconsin solution (UW) by adding one of the protective agents prostaglandin E1 (PGE1), dexamethasone (Dex) or dibutyryl cAMP (Bt2-cAMP), or a combination of these, to the perfusate of rat lungs exposed to 4 ;h of cold ischaemia followed by 1 ;h of reperfusion. Nine modified UW solutions were studied: (1) UW+Dex, (2) UW+PGE1, (3) UW+Bt2-cAMP, (4) UW+Dex×3, (5) UW+PGE1×3, (6) UW+Bt2-cAMP×3, (7) UW+Dex+PGE1, (8) UW+Dex+Bt2-cAMP, (9) UW+PGE1+Bt2-cAMP. These solutions were utilized in individual experiments to assess haemodynamic changes, lung weight gain, the capillary filtration coefficient (Kfc) and pathology in all lungs. 3.The results indicate that lung weight gain and Kfc values were significantly lower than with UW alone in groups 1, 2 and 3, which contained only one additional protective agent. In groups 4, 5 and 6, which contain three times the concentration of each protective agent, both Kfc and lung weight gain were similar to those measured in groups 1, 2 and 3, i.e. lungs were protected but the protection was not dose dependent. In groups 7, 8 and 9, which contained two protective agents, lung weight gain and Kfc were greatly reduced compared with UW alone. Histopathological studies showed similar decreases in the injury profiles of lungs. 4.Although UW contains several antioxidant protective agents such as allopurinol and glutathione, it did not provide effective protection in our ischaemia–reperfusion lung injury model. UW modified with an additive of PGE1, Dex or Bt2-cAMP attenuated ischaemia–reperfusion injury. Furthermore, UW containing two of these protective agents augmented the protection. Among the modified solutions, it appears that UW+PGE1+Bt2-cAMP protects the lungs to a greater extent than all other solutions used in our study. We suggest that preservation solutions containing PGE1-Bt2-cAMP will provide additional protective effects to organs stored for transplantation.

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