Carbon monoxide protects against hepatic ischemia/reperfusion injury by modulating the miR-34a/SIRT1 pathway

• Published in: Biochimica et biophysica acta 2015-07, Vol.1852 (7), p.1550-1559
• Main Authors: Kim, Hyo Jeong, Joe, Yeonsoo, Yu, Jae Kyoung, Chen, Yingqing, Jeong, Sun Oh, Mani, Nithya, Cho, Gyeong Jae, Pae, Hyun-Ock, Ryter, Stefan W., Chung, Hun Taeg
• Format: Article
• Language: English
• Subjects: Animals; Carbon monoxide; Carbon Monoxide - pharmacology; Carbon Monoxide - therapeutic use; Cell Line; Cells, Cultured; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Liver; Liver - blood supply; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miR-34a; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; p53; Reperfusion Injury - metabolism; Reperfusion Injury - prevention & control; SIRT1; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2015.04.017

Hepatic ischemia/reperfusion (I/R) injury can arise as a complication of liver surgery and transplantation. Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, modulates inflammation and apoptosis in response to oxidative stress. SIRT1, which is regulated by p53 and microRNA-34a (miR-34a), can modulate non-alcoholic fatty liver disease, fibrosis and cirrhosis. Since carbon monoxide (CO) inhalation can protect against hepatic I/R, we hypothesized that CO could ameliorate hepatic I/R injury by regulating the miR-34a/SIRT1 pathway. Livers from mice pretreated with CO, or PFT, a p53 inhibitor, displayed reduced production of pro-inflammatory mediators, including TNF-α, iNOS, interleukin (IL)-6, and IL-1β after hepatic I/R injury. SIRT1 expression was increased by CO or PFT in the liver after I/R, whereas acetylated p65, p53 levels, and miR-34a expression were decreased. CO increased SIRT1 expression by inhibiting miR-34a. Both CO and PFT diminished pro-inflammatory cytokines production in vitro. Knockdown of SIRT1 in LPS-stimulated macrophages increased NF-κB acetylation, and increased pro-inflammatory cytokines. CO treatment reduced miR-34a expression and increased SIRT1 expression in oxidant-challenged hepatocytes; and rescued SIRT1 expression in p53-expressing or miR-34a transfected cells. In response to CO, enhanced SIRT1 expression mediated by miR-34a inhibition protects against liver damage through p65/p53 deacetylation, which may mediate inflammatory responses and hepatocellular apoptosis. The miR-34a/SIRT1 pathway may represent a therapeutic target for hepatic injury. •CO inhalation ameliorates hepatic I/R injury in mice.•CO increased SIRT1 expression by inhibiting miR-34a.•CO-mediated increase of SIRT1 expression protects against liver damage through p65/p53 deacetylation.•CO reduces I/R-induced inflammatory responses and apoptotic hepatic injury via miR-34a/SIRT1 pathway.