HO-1/Sesn2 Signaling Pathway Activated By Aleanolic Acid Attenuates Liver I/R Injury

BACKGROUND:During liver surgery such as transplantation and hepatectomy, a period of ischemia and restoration of the blood supply can result in liver ischemia-reperfusion injury (IRI), which causes up to 10% of early liver failure rate and increases the incidence of immune rejection of liver transplantation including both acute and chronic rejection. Numerous studies show that oxidative stress injury is a critical cause of liver IRI, which may initiate the cascade of cell injury, necrosis/apoptosis, and subsequent inflammatory infiltration. Ultimately, Liver function recovery following IR injury is affected by various inflammatory cytokines and growth factors. For the reason, reducing oxidative stress is traditionally thought to be an effective therapeutic approach in the protection from liver IRI.In previous studies, it was thought that oleanolic acid (OA), a natural component of many plant food and medicinal herbs, has potent antioxidant activity and may protect cells and tissues against oxidative stress. The OA’s antioxidant effects seem to be mediated to a great extent through activation of Nrf2 and HO-1 in chronic cyclosporine nephropathy and through PI3K/Akt pathyway in liver injury. Current research indicates that OA has a protective effect in animal models of liver IRI. However there is a lack of research regarding the mechanism for the protective effects of OA in liver IRI.OBJETTVE:This study is designed to investigate whether aleanolic acid attenuates liver I/R injury and the further mechanism of the hepatoprotective effect of OA in liver IRIMETHODS:well-established mice model of partial warm liver IR is used for the study, which an atraumatic clip was used to interrupt the artery/portal vein blood supply to the left/middle liver lobes for 90 min. All animals were divided into eight groups as follow:an I/R group without OA or ZnPP pretreatment (IR, n=6); an I/R group with OA pretreatment (OA, n=6); an I/R group with ZnPP(ZnPP, n=6); an I/R group with O A pretreatment and ZnPP (OA+ZnPP, n=6) and the four sham-operated group. The sham-operated controls didn’t block portal blood flow but the rest of the surgery procedure is the same compared with operation group. All mice were sacrificed at 6 h after portal blood flow reperfusion in the same protocol. Serum samples and liver tissue were collected for the detection of ALT and AST levels and the expression of Sesn2, HO-1,which were measured with Western blotting and RT-PCR.RESULTS:Compared with the IR group and control group, mice in OA pretreatment group had significantly lower levels of serum aminotransferase 6 hours post-operatively (P< 0.05, respectively), milder liver damage and up-regulated anti-oxidative stress signal expressions of HO-1, PI3K/Akt and Sesn2(P<0.05).. Administration of an inhibitor of HO-1, ZnPP, significantly aggravated liver damage (P<0.01), and down-regulated the expression of HO-1 and Sesn2 (P<0.01). OA activated Sesn2 in liver IRI and reduced liver IR injury partially through the HO-1 and Sesn2 signaling pathway.CONCLUSION:These results demonstrate that OA can partially attenuate liver IRI via the HO-1 and Sesn2 up-regulation.