Increased soluble guanylate cyclase activity in the red blood cells of sickle cell patients

Abstract

Summary Activation of soluble guanylate cyclase (sGC) has been reported to up‐regulate γ‐globin gene transcription in erythroid cell lines and primary erythroblasts. sGC is activated by nitric oxide (NO), subsequently catalysing the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP), which mediates various physiological responses. To study the importance of this mechanism in the erythroid cells of sickle cell patients, cGMP levels were measured in the red blood cells (RBC) of normal individuals, steady‐state sickle cell patients (SS) and SS patients on hydroxyurea (HU) therapy (SS + HU). cGMP levels were found to be significantly higher in RBC of SS patients (SS RBC) than in RBC of normal individuals, and were further increased in RBC of SS + HU patients. cGMP levels correlated with fetal haemoglobin (HbF) levels in SS/SS + HU patients, but not with reticulocyte count. Furthermore, NO‐stimulated sGC activity, following incubation of cells with a NO donor, was significantly greater in SS RBC than in normal RBC. These results demonstrate, for the first time, an increased metabolism of NO mediated by sGC in the SS RBC, which is further increased by hydroxyurea. Augmentation of cGMP levels by NO in erythroid cells may constitute a mechanism for induction of HbF and other erythrocyte functions and represent a possible therapeutic target for treatment of sickle cell disease.

Activation of the PI3-K/Akt Pathway Mediates cGMP Enhanced-Neurogenesis in the Adult Progenitor Cells Derived from the Subventricular Zone

“…Consistent with these in vivo data, we now show that incubation of neurospheres with Sildenafil significantly increased neurogenesis. In addition, incubation of neurospheres with Sildenafil increased cGMP levels and 8-Br-cGMP mimicked Sildenafil enhanced neurogenesis, whereas inhibition of sGC, which catalyzes guanosine triphosphate into cGMP (Conran, 2004), reduced Sildenafil-enhanced neurogenesis. Although the biological activity of endogenous cGMP increased by Sildenafil may be different from the exogenous cGMP analog, our data suggest that Sildenafil enhances neurogenesis via increases of cGMP levels and endogenous basal levels of cGMP are required for neurogenesis.…”

Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation

“…Indeed, HU has been reported to induce NO-cGMP signaling in endothelial cells 14 and cGMP levels have been found to be increased in the plasma and red cells of SCD individuals on HU. 21,22 Furthermore, HU may increase NO bioavailability by decreasing hemolysis and, in turn, decreasing NO scavenging by cell-free plasma hemoglobin and arginine scavenging by cell-free arginase. 7 The correlation of SCD/SCDHU neutrophil adhesiveness to markers of the hemolytic rate, hemoglobin levels and reticulocyte counts did not, however, reveal any significant associations with hemolytic rate (results not shown).…”

Nitric oxide synthetic pathway and cGMP levels are altered in red blood cells from end-stage renal disease patients

“…However, along with the study just mentioned, there are only a few studies concerning NO production, RBC-NOS expression, and activation in RBCs from other pathological conditions [23][24][25]. Some of them show an increased RBC-NOS activation in RBCs from sickle cell anemia patients and a significant increase in cGMP levels within RBCs has also been found as compared to healthy subjects [25,26]. Recently, it was shown that NO production was higher in RBCs from patients with type 2 diabetes than in controls [27].…”