*Purpose: To test the therapeutic efficacy of pharmacological inhibition of fatty acid beta-oxidation (FAO) on acute heart allograft survival.

*Methods: We used a heterotopic Balb/c donor heart to C57Bl/6 recipient mouse transplant model and tested the therapeutic efficacy of pharmacological inhibition of the rate-limiting FAO enzyme, carnitine palmitoyltransferase 1 (Cpt1), using the drug etomoxir. We assessed heart allograft survival by direct palpation of the transplanted heart, and assessed rejection by histology and immune cell infiltration. We further assessed immune cell composition in the transplanted heart, native heart, spleen and draining mediastinal lymph node by flow cytometry. Further, we assessed T cell activation by ELISPOT assay on splenocytes from heart transplants treated with vehicle or etomoxir using Balb/c-derived activated antigen-presenting cells (APCs). Finally, we utilized adoptive transfer of CD45.1⁺ monocytes and in vitro monocyte differentiation assays to assess the effects of FAO inhibition in vivo and in vitro.

*Results: Pharmacological inhibition of FAO significantly improved heart allograft survival, while reducing T cell infiltration and activation, and reducing the numbers of dendritic cells and macrophages within transplanted hearts in recipients treated with etomoxir, compared with those treated with vehicle controls. Splenocytes from heart transplanted recipients treated with etomoxir were less reactive to a general stimulus (concanavalin A) or allo-specific stimulus (activated Balb/c APCs). Adoptive transfer of CD45.1⁺ monocytes revealed reduced monocyte-to-macrophage and monocyte-to-DC differentiation in vivo, and in vitro monocyte differentiation assays confirmed this observation.

*Conclusions: Pharmacological inhibition of FAO is a promising therapeutic target that prolongs heart allograft survival, in part, through modulating monocyte differentiation, resulting in reduced T cell activation.

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