The theory that red blood cells (RBCs) generate and release nitric oxide (NO)-like bioactivity has gained considerable interest. However, it remains unclear whether it can be produced by endothelial NO synthase (eNOS), which is present in RBCs, and whether NO can escape scavenging by hemoglobin. The aim of this study was to test the hypothesis that arginase reciprocally controls NO formation in RBCs by competition with eNOS for their common substrate arginine and that RBC-derived NO is functionally active following arginase blockade. We show that rodent and human RBCs contain functional arginase 1 and that pharmacological inhibition of arginase increases export of eNOS-derived nitrogen oxides from RBCs under basal conditions. The functional importance was tested in an ex vivo model of myocardial ischemiareperfusion injury. Inhibitors of arginase significantly improved postischemic functional recovery in rat hearts if administered in whole blood or with RBCs in plasma. By contrast, arginase inhibition did not improve postischemic recovery when administered with buffer solution or plasma alone. The protective effect of arginase inhibition was lost in the presence of a NOS inhibitor. Moreover, hearts from eNOS −/− mice were protected when the arginase inhibitor was given with blood from wildtype donors. In contrast, when hearts from wild-type mice were given blood from eNOS −/− mice, the arginase inhibitor failed to protect against ischemia-reperfusion. These results strongly support the notion that RBCs contain functional eNOS and release NO-like bioactivity. This process is under tight control by arginase 1 and is of functional importance during ischemia-reperfusion.is a biological messenger that is a key regulator of cardiovascular function by inducing vasodilation, inhibition of platelet aggregation, and leukocyte adhesion (1). Reduced bioavailability of endothelium-derived NO is closely associated with development of several cardiovascular diseases including atherosclerosis, ischemia-reperfusion injury, and hypertension. The vascular effects of NO have traditionally been considered to be mediated by endothelium-derived NO after formation by the constitutively expressed endothelial NO synthase (eNOS). An alternative source of NO is nitrite that can be converted to NO in cardiac tissue during ischemia or hypoxia (2-4). In 1996, Stamler and colleagues suggested a role for red blood cells (RBCs) in exporting NO bioactivity and regulating blood flow (5). In this model, RBCs contain NO in the form of S-nitrosylated hemoglobin, which is in equilibrium with small nitrosothiols that are exported preferentially under deoxygenated conditions (5, 6). RBCs thereby provide NO-based vasodilatory activity through S-nitrosothiols when deoxygenated. It was also suggested that the source of RBC NO is eNOS (5). However, it was assumed that eNOS was exclusively vascular in origin, and mechanisms regulating RBC formation and export of NO bioactivity have been a matter of significant debate over the years (7). Another mechanism for ...

Inhibition of arginase protects from myocardial infarction by a mechanism that is dependent on NOS activity and bioavailability of NO by shifting arginine utilization from arginase towards NOS. These findings suggest that targeting of arginase is a promising future therapeutic strategy for protection against myocardial IR injury.

No abstract