• 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.
    • Single-Stranded Oligonucleotide Aptamer Binding to P-Selectin Inhibits Adhesion of Sickle Red Blood Cells and Leukocytes to Endothelial Cells in Sickle Cell Disease Model Mice: Novel Therapeutics for Vaso-occlusive Episodes

      Gutsaeva, Diana R.; Parkerson, James B.; Schaub, Robert G.; Kurz, Jeffrey C.; Head, C. Alvin; Medical College of Georgia; Department of Anesthesiology and Perioperative Medicine (American Society of Hematology, 2009-12)
      Adhesive interactions between circulating red blood cells (RBC), leukocytes, and endothelial cells in post capillary venules have been implicated as a contributing factor to the pathogenesis of vaso-occlusion, the major cause of morbidity and mortality associated with sickle cell disease (SCD). Endothelial cell P-selectin, a member of the selectin family of cell adhesion molecules, plays a key role in leukocyte recruitment as well as in the adhesion of sickle RBC (sRBC) to the endothelium. The expression of P-selectin is elevated in SCD and the interaction of P-selectin and its ligands is likely to contribute to impairment of the microvascular flow and thereby to the development of painful vaso-occlusive episodes. Aptamers, short single-stranded oligonucleotides that fold into complex 3-D structures and bind to ligands, have been developed for a wide range of therapeutic targets. Although anti-P-selectin aptamers have been shown to inhibit leukocyte rolling in vitro and to display efficacy in mouse models for inflammation, anti-adhesion activity of anti-P-selectin aptamers has never been evaluated in SCD.
    • Synergistic Enhancement of Sickle Red Blood Cell Adhesion to Endothelium by Hypoxia and Low Nitric Oxide Bioavailability

      Gutsaeva, Diana R.; Parkerson, James B.; Yerigenahally, Shobha D; Ikuta, Tohru; Head, C. Alvin; Department of Anesthesiology and Perioperative Medicine (American Society of Hematology, 2010-12)
      The mechanisms underlying sickle red blood cell (RBC) adhesion to the endothelium, which constitutes a major pathologic event in sickle cell disease (SCD), are not fully understood. Adhesion of sickle RBCs to endothelial cells is believed to be regulated by multiple hematologic and physiologic factors including fetal hemoglobin levels, leukocyte count, oxygen tension, inflammatory cytokines, and nitric oxide (NO) bioavailability, but the extent to which each parameter contributes to sickle RBC adhesion remains unclear. Our objective was to examine how the adhesion of sickle RBCs to endothelium is affected by hypoxia and NO bioavailability using an in vivo system.
    • 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.