Yu Xiao1, Shouhua Zhang2, Qiang Li1, Zhiwen Liu2, Wenli Mai3, Wen Chen3, Jun Lei2, Huakun Hu4. 1. Department of Anesthesiology, Jiangxi Provincial Children's Hospital, 122 Yangming Road, Nanchang, 330006, Jiangxi Province, China. 2. Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, 330006, Jiangxi Province, China. 3. Department of Oncology, Jiangxi Provincial Cancer Hospital, Nanchang, 330029, China. 4. Department of Anesthesiology, Jiangxi Provincial Children's Hospital, 122 Yangming Road, Nanchang, 330006, Jiangxi Province, China. 15179159272@163.com.
Abstract
BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is a serious complication that occurs upon hypovolemic shock, liver resection, and transplantation. A significant age-dependent difference in the injury response to hepatic I/R in both human and animal models has been reported. Nevertheless, the molecular mechanism is currently unclear. AIMS: To clarify the reason why aged animals or people were more vulnerable to hepatic I/R injury. METHODS: In the present study, we found decreased miR-219a-5p expression in the old mice more vulnerable to hepatic I/R injury. Administrated with agomir-miR-219a-5p diminished the severity of hepatic I/R injury in old mice, as indicated by lower serum ALT and AST, oxidative parameters including MDA, TOA, and OSI, and decreased apoptotic cell number. The effect of miR-219a-5p was also confirmed in the H2O2-induced apoptosis model in AML-12 and NCTC1469 cells. After miR-219a-5p overexpression, two key apoptosis-related proteins Bax and P21, target genes of TP53, were decreased. Furthermore, TP53BP2 interacts with p53 family members and promotes their transcriptional activities toward pro-apoptosis genes. RESULTS: RNA sequencing, western blot, and luciferase reporter assay proved that TP53BP2, a crucial TP53 transcriptional activity enhancer in vivo, was directly regulated by miR-219a-5p. CONCLUSIONS: In summary, our study demonstrated that age-related miR-219a-5p can attenuate hepatic I/R injury through inhibiting TP53BP2 and downstream TP53-dependent apoptosis of hepatic cells in mice.
BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is a serious complication that occurs upon hypovolemic shock, liver resection, and transplantation. A significant age-dependent difference in the injury response to hepatic I/R in both human and animal models has been reported. Nevertheless, the molecular mechanism is currently unclear. AIMS: To clarify the reason why aged animals or people were more vulnerable to hepatic I/R injury. METHODS: In the present study, we found decreased miR-219a-5p expression in the old mice more vulnerable to hepatic I/R injury. Administrated with agomir-miR-219a-5p diminished the severity of hepatic I/R injury in old mice, as indicated by lower serum ALT and AST, oxidative parameters including MDA, TOA, and OSI, and decreased apoptotic cell number. The effect of miR-219a-5p was also confirmed in the H2O2-induced apoptosis model in AML-12 and NCTC1469 cells. After miR-219a-5p overexpression, two key apoptosis-related proteins Bax and P21, target genes of TP53, were decreased. Furthermore, TP53BP2 interacts with p53 family members and promotes their transcriptional activities toward pro-apoptosis genes. RESULTS: RNA sequencing, western blot, and luciferase reporter assay proved that TP53BP2, a crucial TP53 transcriptional activity enhancer in vivo, was directly regulated by miR-219a-5p. CONCLUSIONS: In summary, our study demonstrated that age-related miR-219a-5p can attenuate hepatic I/R injury through inhibiting TP53BP2 and downstream TP53-dependent apoptosis of hepatic cells in mice.
Authors: Jerry E Chipuk; Tomomi Kuwana; Lisa Bouchier-Hayes; Nathalie M Droin; Donald D Newmeyer; Martin Schuler; Douglas R Green Journal: Science Date: 2004-02-13 Impact factor: 47.728
Authors: S Feng; N P Goodrich; J L Bragg-Gresham; D M Dykstra; J D Punch; M A DebRoy; S M Greenstein; R M Merion Journal: Am J Transplant Date: 2006-04 Impact factor: 8.086