Donor simvastatin treatment abolishes rat cardiac allograft ischemia/reperfusion injury and chronic rejection through microvascular protection
| Autor: | Raimo Tuuminen, Katri Koli, Antti I. Nykänen, Usama Abo-Ramadan, Jussi Tikkanen, Karl B. Lemström, Mikko A. I. Keränen, Pertti J. Neuvonen, Rainer Krebs, Simo Syrjälä |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Graft Rejection
Male Simvastatin medicine.medical_treatment Nitric Oxide Synthase Type II Rats Inbred WF 030204 cardiovascular system & hematology Major Histocompatibility Complex 0302 clinical medicine Polyisoprenyl Phosphates Enzyme Inhibitors Heart transplantation 0303 health sciences rho-Associated Kinases Endothelin-1 Gap Junctions 3. Good health medicine.anatomical_structure NG-Nitroarginine Methyl Ester Reperfusion Injury Cardiology medicine.symptom Cardiology and Cardiovascular Medicine medicine.drug medicine.medical_specialty Endothelium Ischemia Inflammation Microcirculation 03 medical and health sciences Physiology (medical) Internal medicine medicine Animals 030304 developmental biology business.industry Endothelial Cells medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Surgery Rats Transplantation Microvessels Heart Transplantation No-Reflow Phenomenon Primary Graft Dysfunction business Reperfusion injury Heme Oxygenase-1 |
| Zdroj: | Circulation. 124(10) |
| ISSN: | 1524-4539 |
| Popis: | 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. Methods and 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. |
| Databáze: | OpenAIRE |
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