• Hydroxyurea induces fetal hemoglobin expression by activating cAMP signaling pathways in a cAMP- and cGMP-dependent manner

      Ikuta, Tohru; Gutsaeva, Diana R.; Parkerson, James B.; Yerigenahally, Shobha D; Head, C. Alvin; Department of Anesthesiology and Perioperative Medicine (American Society of Hematology, 2010-12)
      Here we show that hydroxyurea (HU) induces fetal hemoglobin (HbF) expression by activating the cAMP pathway through two independent mechanisms. Although HU increased both cAMP and cGMP levels in CD34+-derived erythroblasts, only the cAMP pathway was found to be activated. However, HU-induced HbF expression was affected by the activities of both adenylate cyclase (AC) and soluble guanylate cyclase (sGC). HU decreased the expression of cGMP-inhibitable phosphodiesterase (PDE) 3B in a sGC-dependent manner, resulting in activation of the cAMP pathway. Second, HU induced the expression of cyclooxygenase-1 (COX-1) and increased the production of prostaglandin E2 (PGE2), which resulted in activation of the cAMP signaling pathway through AC. HU therapy elevated plasma PGE2 levels in sickle cell patients. These results demonstrate that HU induces HbF expression by activating the cAMP pathway via dual signaling mechanisms.
    • Transcranial Doppler measures in patients with sickle cell disease at high risk for stroke and receiving hydroxyurea: the HyRetro ancillary study

      Adamkiewicz, Thomas; Odo, Nadine; Kutlar, Abdullah; Kwiatkowski, Janet L; Adams, Robert J; School of Medicine; Morehouse College; Department of Anesthesiology and Perioperative Medicine (American Society of Hematology, 2010-12)
      Children with sickle cell disease (SCD) and increased transcranial Doppler sonography velocity measures are at increased risk for stroke. Although chronic transfusion decreases risk tenfold, this form of therapy is burdensome and includes risk of iron overload. Hydroxyurea therapy is effective in preventing SCD complications, although its effect in preventing SCD central nervous system complications is less clear and a matter of current investigation.