Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection Through Microvascular Protection

作者：Tuuminen Raimo; Syrjala Simo; Krebs Rainer; Keranen Mikko A I; Koli Katri; Abo Ramadan Usama; Neuvonen Pertti J; Tikkanen Jussi M; Nykanen Antti I^*; Lemstrom Karl B

来源：Circulation, 2011, 124(10): 1138-U158.

DOI：10.1161/CIRCULATIONAHA.110.005249

• endothelium
• inflammation
• ischemia
• microcirculation
• transplantation

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-1 alpha, 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-beta 1 signaling, and myocardial fibrosis. In vitro, simvastatin inhibited transforming growth factor-beta 1-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. (Circulation. 2011; 124: 1138-1150.)

• 出版日期2011-9-6