Cardioprotective effects of erythrocytes mediated by sGC and release of cGMP

Red blood cells (RBCs) regulate cardiovascular function via a mechanism involving nitric oxide-like bioactivity, but the signaling and the identity of any mediator released by RBCs have remained unknown. We have investigated whether RBCs exposed to hypoxia mediates cardioprotection during ischemia-reperfusion and explored the signaling involved. Administration of hypoxic RBCs or the extracellular supernatant from mouse RBCs exposed to hypoxia to isolated hearts subjected to ischemia-reperfusion improved post-ischemic cardiac function and reduced infarct size. This cardioprotective effect was abolished by blocking sGC in the RBCs or when exposing RBCs from sGC knockout mice to hypoxia, suggesting that RBC sGC is required for the protective effect. Exposure of RBCs to hypoxia resulted in increased extracellular levels of cGMP, and exogenous cGMP mimicked the cardioprotection induced by the supernatant. The protection induced by hypoxic RBCs was dependent on cGMP transport, sensitive to phosphodiesterase 5 and activated cardiomyocyte protein kinase G. Oral administration of nitrate to mice and humans to increase nitric oxide bioactivity further enhanced the cardioprotective effect of RBCs. Pharmacological stimulation of RBC sGC mimicked the cardioprotective effect of hypoxia and reversed the negative effect of RBCs from patients with type 2 diabetes on post-ischemic cardiac function via a mechanism involving release of cGMP and activation of cardiac protein kinase G. It is concluded that RBCs generate and export cGMP as a response to hypoxia mediating cardioprotection via a paracrine effect. This effect can be further augmented by pharmacological stimulation of RBC sGC suggesting a therapeutic target in ischemic heart disease.