Carbon monoxide ameliorates hepatic ischemia/reperfusion injury via sirtuin 1‐mediated deacetylation of high‐mobility group box 1 in rats

Carbon monoxide (CO) exerts protective effects on hepatic ischemia/reperfusion (I/R) injury, but the underlying molecular mechanisms are not fully understood. High mobility group box 1 (HMGB1) is an important mediator of injury and inflammation in hepatic I/R injury. Here, we investigated whether CO could attenuate hepatic I/R injury via inhibition of HMGB1 release, particularly through sirtuin 1 (SIRT1). CO was released by treatment with CO-releasing molecule (CORM)-2. CORM-2-delivered CO ameliorated hepatic I/R injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory responses and less severe I/R-associated histopathologic changes. Treatment with CORM-2 significantly inhibited I/R injury-induced HMGB1 translocation and release. SIRT1 expression was increased by CORM-2 pretreatment. When CORM-2-induced SIRT1 expression was inhibited using EX527, HMGB1 translocation and release were increased and hepatic I/R injury was worsened, while SIRT1 activation by resveratrol reversed this trend. In vitro, CORM-2 reduced hypoxia/reoxygenation-induced HMGB1 translocation and release, which were blocked by SIRT1 inhibition using EX527 or SIRT1 small interfering RNA both in AML12 cells and RAW264.7 macrophages. Moreover, SIRT1 directly interacted with and deacetylated HMGB1. I/R injury increased HMGB1 acetylation, which was abolished by CORM-2 treatment via SIRT1. Conclusion: These results suggest that CO may increase SIRT1 expression, which may decrease HMGB1 acetylation and subsequently reduce its translocation and release, thereby protecting against hepatic I/R injury. This article is protected by copyright. All rights reserved.