دورية
Heme oxygenase‐1 regulates sirtuin‐1–autophagy pathway in liver transplantation: From mouse to human
| العنوان: | Heme oxygenase‐1 regulates sirtuin‐1–autophagy pathway in liver transplantation: From mouse to human |
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| المؤلفون: | Nakamura, Kojiro, Kageyama, Shoichi, Yue, Shi, Huang, Jing, Fujii, Takehiro, Ke, Bibo, Sosa, Rebecca A., Reed, Elaine F., Datta, Nakul, Zarrinpar, Ali, Busuttil, Ronald W., Kupiec‐Weglinski, Jerzy W. |
| المصدر: | American Journal of Transplantation; May 2018, Vol. 18 Issue: 5 p1110-1121, 12p |
| مستخلص: | Liver ischemia–reperfusion injury (IRI) represents a major risk factor of 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 OLTremains unknown. Despite recent data identifying heme oxygenase‐1 (HO‐1) as a putative autophagy inducer, its role in OLTand interactions with sirtuin‐1 (SIRT1), a key autophagy regulator, have not been studied. We aimed to examine HO‐1–mediated autophagy induction in human OLTand in a murine OLTmodel with extended (20 hours) cold storage, as well as to analyze the requirement for SIRT1 in autophagy regulation by HO‐1. Fifty‐one hepatic biopsy specimens from OLTpatients were collected under an institutional review board protocol 2 hours after portal reperfusion, followed by Western blot analyses. High HO‐1 levels correlated with well‐preserved hepatocellular function and enhanced SIRT1/LC3B expression. In mice, HO‐1 overexpression by genetically modified HO‐1 macrophage therapy was accompanied by decreased OLTdamage and increased SIRT1/LC3B expression, whereas adjunctive inhibition of SIRT1 signaling diminished HO‐1–mediated hepatoprotection and autophagy induction. Our translational study confirms the clinical relevance of HO‐1 cytoprotection and identifies SIRT1‐mediated autophagy pathway as a new essential regulator of HO‐1 function in IR‐stressed OLT. This translational study confirms the clinical relevance of heme oxygenase‐1 hepatoprotection and identifies SIRT1‐dependent autophagy signaling as a novel and essential regulator of HO‐1 function in liver transplant under ischemia–reperfusion stress. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 16006135 16006143 |
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| DOI: | 10.1111/ajt.14586 |