Abstract
Terlipressin has been used extensively in the management of certain complications associated with end-stage liver diseases (ESLDs). In our pilot study, terlipressin treatment showed beneficial effects on liver function in patients with decompensated cirrhosis, however whether it plays a role in liver ischemia-reperfusion injury (IRI) remains unknown. Using a mouse nonlethal hepatic IR model, we found terlipressin administration significantly ameliorated IR-induced liver apoptosis, necrosis and inflammation. Furthermore, despite its known effect on visceral vasoconstriction, hemodynamic evaluation of murine hepatic tissue after IR revealed no change of overall hepatic blood flow after terlipressin treatment. Further studies identified the upregulation of vasopressin receptor 1 (V1R) expression on hepatocytes upon IR. In isolated hepatocyte hypoxia/reoxygenation model, the active component of terlipressin, lysine vasopressin, conferred hepatocytes resistant to oxidative stress-induced apoptosis. Mechanistic studies revealed the V1R engagement activated the Wnt/β-catenin/FoxO3a/AKT pathway, which subsequently circumvented the proapoptotic events, thus ameliorated hepatocyte apoptosis. Furthermore, genetic knockdown of V1R expression in hepatocyte cell lines or blockade of this signaling pathway abrogated such protective effect. Conclusion: These data highlight the functional importance of the hepatocyte V1R/Wnt/β-catenin/FoxO3a/AKT pathway in protecting liver from oxidative stress-induced injury.
Highlights
Terlipressin (3’glycyl lysine vasopressin) is a wellrecognized rising star in the medical management of advanced liver cirrhosis and portal hypertension, and has been proven to be the only drug so far which can improve the survival of such patients [1]
In the whole cohort of patients, there was a marked reduction in alanine transaminase (ALT) and aspartate aminotransferase (AST), as well as significantly increased serum albumin (ALB) level after treatment with terlipressin, indicating lessened hepatocyte injury and improved hepatocyte synthetic function
Knockdown of V1R diminished the expression of Wnt3a, β-catenin, phospho-AKT and phospho-forkhead box O3a (FoxO3a), while upregulated total FoxO3a, Bcl-2 interacting mediator of cell death (Bim) and P27 (Figure 7B and S4). These results indicated that lysine vasopressin may protect hepatocytes from oxidative stress-induced apoptosis via V1R-mediated Wnt/β-catenin/
Summary
Terlipressin (3’glycyl lysine vasopressin) is a wellrecognized rising star in the medical management of advanced liver cirrhosis and portal hypertension, and has been proven to be the only drug so far which can improve the survival of such patients [1]. Terlipressin can selectively contract the gastrointestinal www.impactjournals.com/oncotarget capillary bed and dramatically reduce portal pressure, it is mainly used for the treatment of esophageal variceal bleeding. Recent clinical trials reveal terlipressin can achieve good outcomes in the management of other common co-morbidities of advanced portal hypertension such as hepatorenal syndrome, refractory ascites and pleural effusion, making it an ideal drug for integrated treatment of advanced liver cirrhosis and its complications [3]
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