Protein phosphatase 2A activation promotes heart transplant acceptance in mice
Background: While heart transplantation is the standard treatment for heart failure, both acute and chronic transplant rejection frequently occur. Since the modulation of protein phosphatase PP2A activity is critical for tissue and organ homeostasis under physiological and pathophysiological conditions, PP2A may also affect the ability to tolerate transplanted organs. Here we demonstrate that administration of a novel class of small molecule activators of PP2A (SMAPs) prolonged cardiac allograft survival in a mouse heterotopic heart transplantation model. Mechanistically, SMAPs effectively suppressed the inflammatory immune response while increasing Treg population in the allografts, findings corroborated by functional analysis of RNAseq data derived from Tregs of treated splenic tissue. Importantly, SMAPs further prolonged CTLA4-Ig (an immunosuppressive agent utilized in organ transplantation)-induced cardiac rejection tolerance and extended allograft survival. SMAPs also strongly mitigated cardiac allograft vasculopathy as evidenced by a marked reduction of neointimal hyperplasia and smooth muscle cell proliferation. Mechanistic studies implicate SMAPs elicited suppression of MEK/ERK pathways as a unifying mechanism for the aforementioned effects in Tregs and SMCs. These findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation and add knowledge to the phosphatase driven regulation of the immune system in the context of organ transplantation. Overall design: Male C57BL/6 (B6, H-2b) and BALB/c (B/c, H-2d) mice aged 12–16 weeks were used in this study. Donor hearts from BALB/c male mice were transplanted onto the inferior vena cava and aorta in the peritoneal cavity of male C57BL/6J mice. Syngeneic heart graft is defined as a donor heart from C57BL/6J male mice transplanted into C57BL/6J male mice. A 5 mg/kg dose of DT-061 was given intragastrically twice a day beginning on the day of transplantation and continued until the completion of experiments. After 7 days, CD3+CD4+CD25+CD127low cells (Tregs) were sorted by flow cytometry from the spleens of vehicle group and the DT-061 treated group and sent for RNA-seq study.