Treatment with α-melanocyte stimulating hormone preserves calcium regulatory proteins in rat heart allografts

Prevention of graft dysfunction is a major objective in transplantation medicine. Previous research on experimental heart transplantation indicated that treatment with the immunomodulatory peptide α-melanocyte stimulating hormone (α-MSH) improves histopathology, prolongs allograft survival, and reduces expression of the main tissue injury mediators. Because calcium-handling is critical in heart graft function, we determined the effects of transplantation injury and influences of α-MSH treatment on representative calcium regulatory proteins in rat heart allografts. Hearts from Brown Norway rats were transplanted heterotopically into MHC incompatible Lewis rats. Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein kinase C ε (PKCε), sarcoplasmic/endoplasmic reticulum calcium-ATPase 2 (SERCA2a), arrestin-β1 (Arrb1), cholinergic receptor M2 (Chrm2), and inositol 1,4,5-triphosphate receptor 1 (InsP3R1) were examined in: (1) non-transplanted donor hearts; (2) allografts from saline-treated rats; and (3) allografts from rats treated with the synthetic α-MSH analog Nle4-DPhe7-α-MSH (NDP-α-MSH) (100 μg i.p. every 12 h). Transplantation injury was associated with severe reduction in calcium regulatory protein transcription and expression level. NDP-α-MSH administration partly reversed inhibition of protein transcription and almost completely prevented protein loss. Finally, because certain effects of cyclic 3′-5′-adenosine monophosphate (cAMP) signaling on calcium handling in cardiac myocytes depend on activation of exchange protein directly activated by cAMP 1 (Epac1), we determined Epac1 mRNA and protein expression in heart allografts. Transplantation injury markedly reduced Epac1. NDP-α-MSH treatment significantly preserved both Epac1 protein and mRNA in the allografts. Administration of α-MSH or related melanocortins could reduce transplantation-induced dysfunction through protection of heart calcium regulatory proteins.