title: Cardio-protective signalling by glyceryl trinitrate and cariporide in a model of donor heart preservation.
abstract: BACKGROUND
  Storage of donor hearts in cardioplegic solutions supplemented with agents that mimic the ischaemic preconditioning response enhanced their post-reperfusion function. The present study examines the minimisation of cell death and activation of pro-survival signalling directed towards maintenance of mitochondrial homeostasis in hearts arrested and stored in two such agents, glyceryl-trinitrate, a nitric oxide donor and cariporide, (a sodium-hydrogen exchange inhibitor).
  
  
  METHODS
  After baseline functional measurement, isolated working rat hearts were arrested and stored for 6h at 4°C in either Celsior(®), Celsior(®) containing 0.1mg/ml glyceryl-trinitrate, 10μM cariporide or both agents. After reperfusion, function was remeasured. Hearts were then processed for immunoblotting or histology.
  
  
  RESULTS
  Necrotic and apoptotic markers present in the Celsior(®) group post-reperfusion were abolished by glyceryl-trinitrate, cariporide or both. Increased phosphorylation of ERK and Bcl2, after reperfusion in groups stored in glyceryl-trinitrate, cariporide or both along with increased phospho-STAT3 levels in the glyceryl-trinitrate/cariporide group correlated with functional recovery. Inhibition of STAT3 phosphorylation blocked recovery. No phospho-Akt increase was seen in any treatment.
  
  
  CONCLUSIONS
  Activation of signalling pathways that favour mitophagy activation (ERK and Bcl2 phosphorylation) and maintenance of mitochondrial transition pore closure after reperfusion (STAT3 and ERK phosphorylation) were crucial for functional recovery of the donor heart.
authors.affiliation: Division of Cardiac Physiology and Transplantation, Victor Chang Cardiac Research Institute, Darlinghurst NSW 2010, Australia; Current Address: Free Radical Group, Heart Research Institute, Newtown, NSW 2042, Australia; Faculty of Medicine, University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Jair C
authors.initials: JC
authors.lastname: Kwan
authors.affiliation: Division of Cardiac Physiology and Transplantation, Victor Chang Cardiac Research Institute, Darlinghurst NSW 2010, Australia.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: Division of Cardiac Physiology and Transplantation, Victor Chang Cardiac Research Institute, Darlinghurst NSW 2010, Australia; Heart Lung Transplant Unit, St Vincent's Hospital, Darlinghurst NSW 2010 Australia.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Macdonald
authors.affiliation: Division of Cardiac Physiology and Transplantation, Victor Chang Cardiac Research Institute, Darlinghurst NSW 2010, Australia; Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst NSW 2010, Australia; Department of Pharmacology, University of New South Wales, Sydney NSW 2052, Australia. Electronic address: Mark.Hicks@svha.org.au.
authors.forename: Mark
authors.initials: M
authors.lastname: Hicks
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D006146:Guanidines / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D006146:Guanidines; D009124:Muscle Proteins; D019188:Organ Preservation Solutions; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C093373:cariporide; D005996:Nitroglycerin
keywords: Donor heart; Glyceryl trinitrate; Ischaemia reperfusion injury; Mitochondria; Pharmacological conditioning; Sodium hydrogen exchange inhibitor