title: A recombinant human neuregulin-1 peptide improves preservation of the rodent heart after prolonged hypothermic storage.
abstract: BACKGROUND
  Donor hearts are subjected to ischemia-reperfusion injury during transplantation. Recombinant human neuregulin (rhNRG)-1 peptide attenuates myocardial injury in various animal models of cardiomyopathy. Supplementing the organ-storage solution, Celsior (C), with glyceryl trinitrate (GTN) and cariporide improves cardiac preservation after hypothermic storage. We hypothesized that the addition of rhNRG-1 to C would improve cardiac preservation after hypothermic storage and provide incremental benefit in combination with GTN and cariporide.
  
  
  METHODS
  An isolated working rat heart model was used. To assess the effect of rhNRG-1, hearts were stored for 6 hr at 4°C in C ± rhNRG-1 (14 nM). To assess the effect of using a combination of prosurvival kinase activators on cardiac preservation, the ischemic storage time was extended to 10 hr and hearts stored in C ± rhNRG-1 (14 nM) ± GTN (0.1 mg/mL) ± Cariporide (10 μM). Hearts were subsequently reperfused, cardiac function remeasured, and tissue collected for protein analysis and immunohistochemistry. Optimal timing of rhNRG-1 administration was also assessed.
  
  
  RESULTS
  rhNRG-1 supplemented C improved functional recovery after 6 hr of storage (cardiac output recovery [mean ± SEM]: control 1.4% ± 0.6%; rhNRG-1+C 21.1% ± 7.9%; P<0.05). After 10-hr storage, no improvement in functional recovery was observed with rhNRG-1, GTN, or cariporide alone; however, GTN combined with cariporide did improve recovery (P<0.01), which was further enhanced by the addition of rhNRG-1 (P<0.01). Functional improvements were accompanied by increased phosphorylation of Akt, ERK1/2, STAT3, and GSK-3β and reduced cleaved caspase-3 (P<0.01).
  
  
  CONCLUSIONS
  rhNRG-1 given together with other activators of prosurvival pathways improves preservation of the rat heart and shows promise for increasing the cold-ischemic life of donor hearts in transplantation.
authors.affiliation: Heart and Lung Transplant Unit, St Vincent's Hospital and Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jabbour
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.forename: Jair
authors.initials: J
authors.lastname: Kwan
authors.forename: Alasdair
authors.initials: A
authors.lastname: Watson
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Min Ru
authors.initials: MR
authors.lastname: Qiu
authors.forename: Xifu
authors.initials: X
authors.lastname: Liu
authors.forename: Ming Dong
authors.initials: MD
authors.lastname: Zhou
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
authors.forename: Mark
authors.initials: M
authors.lastname: Hicks
authors.forename: Peter S
authors.initials: PS
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002302:Cardiac Output; D050377:Cold Ischemia; D004187:Disaccharides; D004573:Electrolytes; D005971:Glutamates; D005978:Glutathione; D006146:Guanidines; D006321:Heart; D016027:Heart Transplantation / Q000473:pathology / Q000502:physiology; D006639:Histidine; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008353:Mannitol; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D020890:Neuregulin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D005996:Nitroglycerin; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones; D013997:Time Factors
chemical_list: C088453:Celsior; D004187:Disaccharides; D004573:Electrolytes; D005971:Glutamates; D006146:Guanidines; C094131:NRG1 protein, human; D020890:Neuregulin-1; D019188:Organ Preservation Solutions; D011994:Recombinant Proteins; D013450:Sulfones; D008353:Mannitol; D006639:Histidine; C093373:cariporide; D005996:Nitroglycerin; D005978:Glutathione