Background. Heart transplantation is the most effective therapy to prolong life expectancy in patients with end-stage heart failure. However, despite much progress in the field, allograft survival has not improved and chronic allograft vasculopathy (CAV) still limits long-term allograft survival, those molecular pathogenesis remain largely unknown. MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally and are emerging as master regulators of the immune response.

Methods. We used a well-characterized murine model of CAV, the minor MHC Class II mismatch bm12 into C57BL/6 model, to explore the miRnome in CAV.

Results. We first profiling the miRnome in human and murine transplanted hearts. We identified 192 miRNAs that appeared specifically up- or downregulated in murine transplanted allograft. 29 of these miRNAs were upregulated in the syngeneic as well. Among the remaining 163 miRNAs, miR-21 was the most highly expressed in CAV with a 20-fold increase compared to syngeneic bm12 transplanted hearts. The data was confirmed in human transplanted heart as well. Targeting miR-21 with a specific anti-miR-21 oligonucleotides promotes long-term allograft survival in 100% of bm12 into B6 cardiac transplanted mice (compared to control anti-miR). This indefinite survival was associated with a reduced macrophage infiltration and fibrosis. Interestingly, macrophage appeared highly expressing miR-21 and in vivo injection of Cy3-labeled anti-miR-21 oligonucleotides showed a complete macrophage uptake. Anti-miR-21 oligonucleotides, reshape macrophage phenotype, reduced phagocytic and migration macrophage capacity, with no effect on allopresentation ability. The conditional deletion of miR-21 with the use of the miR-21^floxLysM^Cre B6 mice is ongoing to finally confirm the role of miR-21 in CAV.

Conclusion. Macrophage miR-21 upregulation is evident in CAV and targeting miR-21 with a specific anti-miR-21 oligonucleotides, may represent a novel therapeutic tool to abrogate the onset of CAV.

CITATION INFORMATION: Usuelli V, Ben Nasr M, D'Addio F, Kaifeng L, Borgese L, Potena L, Solini A, Rossi C, Secchi A, Corradi D, Chau N, Fiorina P. miR-21 in Chronic Allograft Vasculopathy. Am J Transplant. 2016;16 (suppl 3).

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