Liver ischemia-reperfusion injury (IRI) represents a major risk factor for early graft dysfunction and a key obstacle to expanding the donor pool in orthotopic liver transplantation (OLT). Although graft autophagy is essential for resistance against hepatic IRI, its significance in clinical OLT remains unknown. Despite recent data identifying heme oxygenase-1 (HO-1) as a putative autophagy inducer, its role in OLT settings and putative interactions with Sirtuin-1 (SIRT1), a key autophagy regulator, have not been studied. We aimed to examine HO-1 mediated autophagy induction in human OLT and in a murine OLT model with extended cold storage, as well as to analyze the requirement for SIRT1 in autophagy regulation by HO-1. Fifty-one hepatic human biopsies from OLT patients were collected under an IRB protocol at 2h post-reperfusion, followed by Western blot analyses. HO-1 levels in post-reperfusion human OLT negatively correlated with serum ALT levels at POD1 (r=-0.3306, p=0.0178), while positively with SIRT1 (r=0.4229, p=0.0020) and LC3B (r=0.3594, p=0.0096). Recipients with high HO-1 expression (n=25) were associated with decreased serum ALT levels at POD1 (255±34 vs 809±367 IU/L, p=0.0373), superior post-transplant survival (2-year: 92.6% vs 80.7%), lower frequency of early graft dysfunction (3.8% vs 8.0%) and post-OLT rejection episodes (3.8% vs 16.0%) as compared to those with low HO-1 levels (n=26). In a mouse OLT model, bone marrow derived macrophages (BMMs, 5[times]10⁶) transfected with Ad-HO-1 or Ad-β-gal (2.5[times]10⁹ pfu) were infused directly into liver grafts via portal vein immediately prior to reperfusion. Adoptive transfer of HO-1 overexpressing BMM was accompanied by attenuated OLT damage as evidenced by serum ALT levels and Suzuki's histological grading of IRI (p<0.05). HO-1 overexpressed macrophage treatment decreased Ly6G+ cell trafficking and frequency of TUNEL+ cells (p<0.05) in OLT, while increased hepatic SIRT1/LC3B expression, Moreover, adjunctive pharmacological inhibition of SIRT1 in HO-1 overexpressing OLT diminished hepatoprotection and autophagy induction. In conclusion, our translational study confirms the clinical relevance of HO-1 cytoprotection and identifies SIRT1-mediated autophagy pathway as a new and essential regulator of HO-1 function in IR-stressed OLT.

CITATION INFORMATION: Nakamura K., Kageyama S., Yue S., Aziz A., Ito T., Oncel D., Ke B., Sosa R., Reed E., Kaldas F., Busuttil R., Kupiec-Weglinski J. HO-1 Regulates SIRT1– Autophagy Pathway in Liver Transplantation: From Mouse-to-Human Am J Transplant. 2017;17 (suppl 3).

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