title: Donor simvastatin treatment abolishes rat cardiac allograft ischemia/reperfusion injury and chronic rejection through microvascular protection.
abstract: BACKGROUND
  Ischemia/reperfusion injury may have deleterious short- and long-term consequences for cardiac allografts. The underlying mechanisms involve microvascular dysfunction that may culminate in primary graft failure or untreatable chronic rejection.
  
  
  RESULTS
  Here, we report that rat cardiac allograft ischemia/reperfusion injury resulted in profound microvascular dysfunction that was prevented by donor treatment with peroral single-dose simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase and Rho GTPase inhibitor, 2 hours before graft procurement. During allograft preservation, donor simvastatin treatment inhibited microvascular endothelial cell and pericyte RhoA/Rho-associated protein kinase activation and endothelial cell-endothelial cell gap formation; decreased intragraft mRNA levels of hypoxia-inducible factor-1α, inducible nitric oxide synthase, and endothelin-1; and increased heme oxygenase-1. Donor, but not recipient, simvastatin treatment prevented ischemia/reperfusion injury-induced vascular leakage, leukocyte infiltration, the no-reflow phenomenon, and myocardial injury. The beneficial effects of simvastatin on vascular stability and the no-reflow phenomenon were abolished by concomitant nitric oxide synthase inhibition with N-nitro-l-arginine methyl ester and RhoA activation by geranylgeranyl pyrophosphate supplementation, respectively. In the chronic rejection model, donor simvastatin treatment inhibited cardiac allograft inflammation, transforming growth factor-β1 signaling, and myocardial fibrosis. In vitro, simvastatin inhibited transforming growth factor-β1-induced microvascular endothelial-to-mesenchymal transition.
  
  
  CONCLUSIONS
  Our results demonstrate that donor simvastatin treatment prevents microvascular endothelial cell and pericyte dysfunction, ischemia/reperfusion injury, and chronic rejection and suggest a novel, clinically feasible strategy to protect cardiac allografts.
authors.affiliation: Transplantation Laboratory, Haartman Institute, P.O. Box 21 (Haartmaninkatu 3), FIN-00014, University of Helsinki, Helsinki, Finland.
authors.forename: Raimo
authors.initials: R
authors.lastname: Tuuminen
authors.forename: Simo
authors.initials: S
authors.lastname: Syrjälä
authors.forename: Rainer
authors.initials: R
authors.lastname: Krebs
authors.forename: Mikko A I
authors.initials: MA
authors.lastname: Keränen
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
authors.forename: Usama
authors.initials: U
authors.lastname: Abo-Ramadan
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Tikkanen
authors.forename: Antti I
authors.initials: AI
authors.lastname: Nykänen
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D019332:Endothelin-1 / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D017629:Gap Junctions / Q000187:drug effects / Q000201:enzymology; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D008285:Major Histocompatibility Complex / Q000187:drug effects; D008297:Male; D055806:Microvessels / Q000187:drug effects* / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D054318:No-Reflow Phenomenon / Q000517:prevention & control; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D055031:Primary Graft Dysfunction / Q000201:enzymology / Q000517:prevention & control*; D051381:Rats; D011920:Rats, Inbred WF; D015427:Reperfusion Injury / Q000517:prevention & control*; D019821:Simvastatin / Q000627:therapeutic use*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011106:Polyisoprenyl Phosphates; D019821:Simvastatin; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D054460:rho-Associated Kinases; C002963:geranylgeranyl pyrophosphate; D019331:NG-Nitroarginine Methyl Ester