Carbon monoxide protects against hepatic ischemia/reperfusion injury by modulating the miR-34a/SIRT1 pathway.
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.
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
Hyo Jeong
HJ
Kim
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
Yeonsoo
Y
Joe
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
Jae Kyoung
JK
Yu
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
Yingqing
Y
Chen
Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
Sun Oh
SO
Jeong
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
Nithya
N
Mani
Department of Anatomy, School of Medicine, and Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea.
Gyeong Jae
GJ
Cho
Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
Hyun-Ock
HO
Pae
Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA.
Stefan W
SW
Ryter
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea. Electronic address: chung@ulsan.ac.kr.
Hun Taeg
HT
Chung
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D053583:Interleukin-1beta; D015850:Interleukin-6; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
Carbon monoxide; Liver; SIRT1; miR-34a; p53