title: Dimethyloxalylglycine treatment of brain-dead donor rats improves both donor and graft left ventricular function after heart transplantation.
abstract: OBJECTIVE
  Hypoxia inducible factor (HIF)-1 pathway signalling has a protective effect against ischemia/reperfusion injury. The prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) activates the HIF-1 pathway by stabilizing HIF-1α. In a rat model of brain death (BD)-associated donor heart dysfunction we tested the hypothesis that pre-treatment of brain-dead donors with DMOG would result in a better graft heart condition.
  
  
  METHODS
  BD was induced in anesthetized Lewis rats by inflating a subdurally placed balloon catheter. Controls underwent sham operations. Then, rats were injected with an intravenous dose of DMOG (30 mg/kg) or an equal volume of physiologic saline. After 5 hours of BD or sham operation, hearts were perfused with a cold (4°C) preservation solution (Custodiol; Dr. Franz Köhler Chemie GmbH; Germany), explanted, stored at 4°C in Custodiol, and heterotopically transplanted. Graft function was evaluated 1.5 hours after transplantation.
  
  
  RESULTS
  Compared with control, BD was associated with decreased left ventricular systolic and diastolic function. DMOG treatment after BD improved contractility (end-systolic pressure volume relationship E'max: 3.7 ± 0.6 vs 3.1 ± 0.5 mm Hg/µ1; p < 0.05) and left ventricular stiffness (end-diastolic pressure volume relationship: 0.13 ± 0.03 vs 0.31 ± 0.06 mm Hg/µ1; p < 0.05) 5 hours later compared with the brain-dead group. After heart transplantation, DMOG treatment of brain-dead donors significantly improved the altered systolic function and decreased inflammatory infiltration, cardiomyocyte necrosis, and DNA strand breakage. In addition, compared with the brain-dead group, DMOG treatment moderated the pro-apoptotic changes in the gene and protein expression.
  
  
  CONCLUSIONS
  In a rat model of potential brain-dead heart donors, pre-treatment with DMOG resulted in improved early recovery of graft function after transplantation. These results support the hypothesis that activation of the HIF-1 pathway has a protective role against BD-associated cardiac dysfunction.
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany; Heart and Vascular Center, Semmelweis University, Budapest, Hungary. Electronic address: phegedues@gmail.com.
authors.forename: Péter
authors.initials: P
authors.lastname: Hegedűs
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sevil
authors.initials: S
authors.lastname: Korkmaz-Icöz
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Radovits
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Mayer
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Samer
authors.initials: S
authors.lastname: Al Said
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Paige
authors.initials: P
authors.lastname: Brlecic
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Merkely
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000098:blood supply; D004195:Disease Models, Animal; D016027:Heart Transplantation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D014019:Tissue Donors; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
chemical_list: D000600:Amino Acids, Dicarboxylic; C040947:oxalylglycine
keywords: DMOG; HIF-1; graft function; heart transplantation; ischemia-reperfusion injury