Suppression of fibroblastic activity prolongs cardiac transplant survival through targeting their ATG5 expression

BACKGROUND: Cardiofibroblasts are closely involved in the process of ischemia and inflammation. Nevertheless, the role of cardiofibroblasts remains unknown in heart transplantation. METHODS: Syngeneic and allogeneic heterotopic cardiac transplantations were performed using C57BL/6 or BALB/c donors for BALB/c recipients through different treatments. Some mice were used to observe the survival of the cardiac grafts. Quantitative polymerase chain reaction, Western blotting, flow cytometry, and immunofluorescence staining were used to identify the fibroblast function in heart grafts. RESULTS: Our study revealed that cardiac fibroblasts were activated and transformed into myofibroblasts. In the myofibroblasts of heart allografts, the expression levels of ATG5, ATG7, and microtubule-associated protein light chain 3-II were increased. Conditional deletion of ATG5 in donor myofibroblasts prolonged heart graft survival, reduced infiltration of inflammatory cytokines (including interleukin-6, interleukin-1β, tumor necrosis factor-α, and interleukin-18), and inhibited CD8 CONCLUSIONS: Significant prolongation of cardiac allograft survival might be achieved by suppressing the activity of cardiofibroblasts, which could be effectively regulated by targeting fibroblastic ATG5, a critical component of autophagy.