Date: Tuesday, June 14, 2016
Session Time: 2:30pm-4:00pm
Presentation Time: 2:42pm-2:54pm
Location: Room 313
Background/Aim: The mechanism by which macrophage heme oxygenase-1 (HO-1)-Sirtuin1 (SIRT1) signaling promotes resistance against inflammation response in liver ischemia-reperfusion injury (IRI) remains elusive. As tumor suppressor protein p53 may be critical in macrophage activation, we have analyzed how macrophage HO-1/SIRT1/p53 axis affects hepatoprotection in liver IRI. Methods/Results: Livers in groups of wild type (WT) and myeloid specific HO-1 transgenic (HO-1TG) mice (C57/BL6) were subjected to partial warm ischemia (90 min) followed by reperfusion (6hr). Upregulation of myeloid HO-1 attenuated the severity of hepatic IRI, as compared to WT controls (sAST: 5,074±2,986 vs. 13,927±2,704 IU/L; p<0.05, n=4-7). Western analysis showed increased levels of HO-1, SIRT1, p19, p53, MDM2 and decreased expression of p-Stat1, p-IkBa and iNOS in IR-stressed HO-1TG livers. This correlated with enhanced RT-PCR expression of SIRT1, Noxa, and p21 and lower levels of IRI cytokine signature (MCP1, TNFα, IL-1β, CXCL10) in HO-1TG livers (p<0.05). Higher levels of SIRT1, p19, p53, MDM2, PUMA, and lower level of p-Stat1 in HO-1TG bone marrow-derived macrophage (BMM) cultures were abolished after transfection of HO-1TG macrophages with SIRT1-siRNA. Then, we asked how pretreatment with SIRT-1 activator, resveratrol (Res) may affect the severity of liver IRI in myeloid-specific HO-1 knockout (HO-1 KO) vs. FLOX-control (Con) mice. While myeloid-specific HO-1 deletion worsened IRI, Res treatment has rescued HO-1 deficient livers from IR-damage (sAST: Con – 10,764±3,238; HO-1KO – 16,379±3,239; HO-1 KO+Res – 6,946±999 IU/L; p<0.05, n=4-6). Adjunctive Res restored otherwise suppressed cytoprotective signaling (SIRT1, p19, p53, and MDM2) in HO-1 deficient livers, data supported by RT-PCR analysis of IRI cytokine signature (p<0.05). Addition of Res to HO-1-deficient BMM cultures restored SIRT1, p19, p53, MDM2, PUMA, Noxa, p21 expression while depressing p-Stat1, TNFα, MCP1, iNOS, IL-1β and IL-12. Res upregulated p19/p53/MDM2 expression in WT BMM cultures while p19-siRNA transfection abolished the ability of Res to induce p53. Conclusion: Macrophage SIRT1 upregulates p53 via p19 signaling. Myeloid cell-specific HO-1/SIRT1/p53 axis regulates inflammation and promotes hepatoprotection in IR-stressed livers.
CITATION INFORMATION: Nakamura K, Zhang M, Ke B, Kageyama S, Busuttil R, Araujo J, Kupiec-Weglinski J. HO-1/SIRT1/p53 Axis Regulates Macrophage Activation and Attenuates Liver Ischemia-Reperfusion Injury in Mice. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Nakamura K, Zhang M, Ke B, Kageyama S, Busuttil R, Araujo J, Kupiec-Weglinski J. HO-1/SIRT1/p53 Axis Regulates Macrophage Activation and Attenuates Liver Ischemia-Reperfusion Injury in Mice. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/ho-1sirt1p53-axis-regulates-macrophage-activation-and-attenuates-liver-ischemia-reperfusion-injury-in-mice/. Accessed January 24, 2021.
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