The cardioprotective effect of hypoxia is mediated by RBC sGC and export of cGMP.
hypoxia, IR injury
HYPOXIC, HYPOXIA
Having determined that a cardioprotective factor was released from RBCs during hypoxia, we next sought to determine the nature of this compound. The focus was directed toward sGC-cGMP as this pathway has been shown to be present in RBCs. To determine the involvement of sGC, we exposed RBCs collected from mice lacking the α1-subunit of sGC (GC KO mice) to hypoxia and the supernatant was administered to hearts from WT mice. The supernatant from these RBCs exposed to hypoxia failed to protect the hearts against IR injury, strongly suggesting that RBC sGC played a key role in cardioprotection (Having confirmed that RBC sGC was responsible for the observed effects, we next performed experiments to determine if cGMP, the product of sGC, is exported from the RBC. To determine the involvement of cGMP in the cardioprotective effect of the supernatant from hypoxic RBCs, the cGMP hydrolyzing enzyme phosphodiesterase 5 (PDE5) was administered to the supernatant before administration of the supernatant to the isolated heart. The cardioprotective effect in the presence of PDE5 was compared to a control group given supernatant from RBCs exposed to hypoxia without addition of PDE5 and performed during the same time period. Importantly, administration of PDE5 abolished the cardioprotective effect of the supernatant from hypoxic RBCs (