AAV-mediated expression of AP-1 neutralizing RNA decoy oligonucleotides attenuates transplant vasculopathy in mouse aortic allografts

Abstract Transplant vasculopathy (TV), characterized by obstructive lesions in affected vessels represents one of the long-term complications of cardiac transplantation. Activation of the transcription factor activator protein-1 (AP-1) is implicated in smooth muscle cells (SMC) phenotypic switch from contractile to synthetic function, increasing migration and proliferation rate of these cells. We hypothesize that adeno-associated virus (AAV)-mediated delivery of a RNA hairpin AP-1 decoy oligonucleotide (dON) might effectively ameliorate TV severity in a mouse aortic allograft model. Aortic allografts from DBA/2 mice ex vivo transduced with modified AAV9-SLR carrying a targeting peptide within the capsid surface were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg BW) was administered daily. AP-1 dONs were intracellularly expressed in the graft tissue as small hairpin RNA proved by fluorescent in situ hybridization. Explantation after 30 days and histomorphometric evaluation revealed that AP-1 dON treatment significantly reduced intima-to-media ratio by 41.5% (p