Sacubitril suppresses experimental chronic heart allograft vasculopathy.

Abstract

Chronic allograft vasculopathy limits graft and recipient survival after heart transplantation despite modern immune suppression. We examined the effect of sacubitril, an inhibitor of neprilysin neutral endopeptidase activity, on the progression of chronic allograft vasculopathy in HY-antigen-mismatched mouse heart transplantation. We found that sacubitril treatment of the recipient markedly blunted the progressive occlusion of the coronary arterial lumen versus the vehicle control. The proteome of the heart grafts was characterized, and notably identifies differential increased expression of several serine protease inhibitors, decreased transforming growth factor-beta superfamily pathway constituents, and matrix proteins among sacubitril-treated recipients. We observed reduced immune cell infiltration of the allograft, associated with suppression of graft vascular endothelial cell Cx3cl1 and Vcam1 expression among the sacubitril-treated recipients. Further, graft expression of proreparative apelin was increased, and endothelial cell-mesenchymal transdifferentiation was suppressed. In vitro, candidate signaling pathways via glucagon-like protein-1 and atrial natriuretic peptide receptor, but not apelin receptor, agonists phenocopied the effect of sacubitril in vivo. The results highlight direct and indirect proteinase inhibitory and favorable anti-inflammatory effects of sacubitril treatment that limit maladaptive repair of the graft vasculature.