Background/Aim: Although the efficacy of heme oxygenase-1 (HO-1) to combat liver ischemia-reperfusion injury (IRI) in animal models is well-established, cell-specific HO-1 function and mechanisms of hepatoprotection remain to be elucidated. Although increased HO-1 levels in human donor livers correlated with augmented liver transplant injury (Geuken, 2005), the role of post-transplant HO-1 expression has not been defined. In this study, we focused on the function of myeloid-specific HO-1 in mouse IRI models and its clinical relevance. Methods/Results: [Human] Liver biopsies (Bx) from twenty-one adult primary liver transplant patients (2h post-reperfusion) were divided into “high” (n=11) vs. “low” (n=10) HO-1 expression groups. The "low" HO-1 group had higher sALT levels at POD1 – POD5 (p<0.05) and inferior outcomes (survival: 60% vs. 100%, p=0.0221), with median follow-up of 712 days (rage, 27-1009 days). Human liver Bx with “low” HO-1 levels showed increased (p<0.05) cleaved caspase 3 but diminished (p<0.05) SIRT1, p53 and MDM2 expression pattern (Western blots). Of note, HO-1 was specifically expressed by liver graft-infiltrating CD68+ cells (immunofluorescence). [Mouse] Groups of myeloid-specific HO-1 knockout (mHO-1 KO) and FLOX control (Con) mice (n=4-6/gr) were subjected to partial hepatic warm ischemia (90min) followed by reperfusion (6h). Compared to Con, mHO-1 deficiency exacerbated hepatocellular damage (p<0.05), evidenced by sALT levels, Suzuki's histological grading and frequency of TUNEL+ cells; while exhibiting suppressed levels of SIRT1, p53 and its downstream signaling genes (MDM2, Noxa). Interestingly, pretreatment with SIRT1 activator (Resveratrol) restored SIRT1/p53 expression and rescued liver function in otherwise IRI-susceptible mHO-1 KO livers (sALT/Suzuki/TUNEL, p<0.05). Consistent with in vivo data, disruption of HO-1 signaling in LPS-activated bone marrow-derived macrophage (BMM) cultures suppressed SIRT1, p53, MDM2 and Noxa, while enhancing p-Stat1, iNOS, TNFα, MCP1 and IL1β levels. This pattern was reversed after addition of Resveratrol to HO-1 deficient BMM culture. Conclusion: Myeloid HO-1 orchestrates IR-stressed hepatocellular function via SIRT1/p53 signaling, with implications for novel therapeutic strategies in liver transplant patients.

CITATION INFORMATION: Nakamura K, Zhang M, Ke B, Kageyama S, Datta N, Zarrinpar A, Busuttil R, Araujo J, Kupiec-Weglinski J. Myeloid HO-1 Orchestrates Liver Graft Function via SIRT1/p53 Signaling: From Mouse-to-Human. Am J Transplant. 2017;17 (suppl 3).

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