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

Shoichi Kageyama, Kojiro Nakamura, Bibo Ke, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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). Consistent with our murine findings, human livers characterized by high NICD were relatively IRI resistant, as shown by serum alanine aminotransferase (ALT) levels at day 1 post-OLT. Our study documents the efficacy of SER–Notch1 signaling in mouse OLT and highlights the protective function of Notch1 in liver transplant patients.

Original languageEnglish (US)
Pages (from-to)1755-1763
Number of pages9
JournalAmerican Journal of Transplantation
Issue number7
StatePublished - Jul 2018


  • animal models: murine
  • basic (laboratory) research/science
  • immunobiology
  • Ischemia-reperfusion injury (IRI)
  • liver disease: immune/inflammatory
  • liver transplantation/hepatology
  • macrophage/monocyte biology
  • tissue injury and repair
  • translational research/science

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)


Dive into the research topics of 'Serelaxin induces Notch1 signaling and alleviates hepatocellular damage in orthotopic liver transplantation'. Together they form a unique fingerprint.

Cite this