Aquaporin 4 blockade is a novel strategy targeting ischemia/reperfusion injury in heart transplantation (TRAN1P.942)

Abstract Aquaporin 4 (AQP4) is the major water channel in the brain and its absence reduces brain edema in murine models of stroke.Recently, human and mouse cardiomyocytes were shown to express AQP4. Our goal was to test whether therapeutic inhibition of AQP4 reduces IRI and improves cardiac allografts survival. B6 mice were transplanted with BALB/c heart allografts subjected to 8 h of cold ischemia. Donors received AQP4 inhibitor 0.5h before harvest; hearts were perfused with and stored for 8 h on ice with the inhibitor. Recipients were given AQP4 inhibitor every 6h for 5 days. In the absence of additional immunosuppression, treatment with AQP4 inhibitor significantly prolonged heart allograft survival (MST 2d, n=24 vs. 6 d, n=5), decreased early T cell infiltration and the intragraft expression of IFNγ, granzyme B, perforin, FASL, CXCR3, ICOS, and CXCL10 in comparison to untreated controls. The frequencies of donor-reactive spleen cells secreting IFNγ in recipients treated with AQP4 inhibitor were also four fold lower than those in untreated controls. Blocking AQP4 during allograft storage and early after transplantation prolongs the survival of fully MHC-mismatched heart allografts subjected to 8 h CIS. The graft prolongation is associated with the reduced early memory T cell infiltration into the graft and decreased anti-donor responses. Our data identify AQP4 as a promising therapeutic target to diminish the detrimental effects of prolonged CIS on transplant outcome.