Serelaxin induces Notch1 signaling and alleviates hepatocellular damage in orthotopic liver transplantation

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Shoichi KageyamaJerzy W Kupiec-Weglinski

Abstract

Liver ischemia-reperfusion injury (IRI) represents a risk factor for early graft dysfunction and an obstacle to expanding donor pool in orthotopic liver transplantation (OLT). We have reported on the crucial role of macrophage Notch1 signaling in mouse warm hepatic IRI model. However, its clinical relevance or therapeutic potential remain unknown. Here, we used Serelaxin (SER), to verify Notch1 induction and putative hepatoprotective function in ischemia-reperfusion-stressed OLT. C57BL/6 mouse livers subjected to extended (18-hour) cold storage were transplanted to syngeneic recipients. SER treatment at reperfusion ameliorated IRI, improved post-OLT survival, decreased neutrophil/macrophage infiltration, and suppressed proinflammatory cytokine programs, while simultaneously increasing Notch intracellular domain (NICD) and hairy and enhancer of split 1 (Hes1) target genes. In bone marrow-derived macrophage cultures, SER suppressed proinflammatory while enhancing antiinflammatory gene expression concomitantly with increased NICD and Hes1. Hepatic biopsies from 21 adult primary liver transplant patients (2 hours postreperfusion) were divided into low-NICD (n = 11) and high-NICD (n = 10) expression groups (western blots). Consisten...Continue Reading

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Citations

Mar 24, 2018·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·James F Markmann
Jan 23, 2020·International Journal of Molecular Sciences·Lina JakubauskienePeter Schemmer
Feb 7, 2020·The Journal of Clinical Investigation·Kojiro NakamuraJerzy W Kupiec-Weglinski
Apr 16, 2020·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Junbin ZhouXiao Xu
Jul 23, 2019·The Journal of Clinical Investigation·Kojiro NakamuraJerzy W Kupiec-Weglinski
Oct 12, 2019·Current Transplantation Reports·Kojiro NakamuraJerzy W Kupiec-Weglinski
Jun 9, 2021·Biochimie·Devaraj Ezhilarasan

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