Combined Donor Simvastatin and Methylprednisolone Treatment Prevents Ischemia-Reperfusion Injury in Rat Cardiac Allografts Through Vasculoprotection and Immunomodulation

Abstract

Ischemia-reperfusion injury (IRI) and allograft dysfunction remain as two of the major clinical challenges after heart transplantation. Here, we investigated the effect of donor treatment with simvastatin and methylprednisolone on microvascular dysfunction and immunomodulation during IRI in rat cardiac allografts subjected to prolonged ischemia time. The DA rats received simvastatin, methylprednisolone, or both 2 hr before heart donation. The allografts were subjected to 4-hr hypothermic preservation and transplanted to the fully major histocompatibility complex-mismatched WF rat recipients. Six hours after reperfusion, donor treatment either with simvastatin alone or with high dose of methylprednisolone alone or in combination with simvastatin and methylprednisolone significantly reduced cardiac troponin T release and the number of allograft infiltrating ED1 macrophages MPO neutrophils. However, the combination donor treatment was superior in the prevention of IRI and significantly prolonged allograft survival. Donor simvastatin treatment inhibited allograft microvascular RhoA GTPase pathway activation, whereas methylprednisolone prevented activation of innate immune response and mRNA expression of hypoxia-inducible factor-1α and its multiple target genes. Our results show that donor treatment in combination with simvastatin and methylprednisolone prevents IRI and has beneficial effect on allograft survival in rat cardiac allografts. Minimizing microvascular injury and the activation of innate immunity may offer a novel therapeutic strategy to expand the donor pool and furthermore improve the function of the marginal donor organs.