Browsing Department of Anesthesiology and Perioperative Medicine: Faculty Research and Presentaions by Authors
Hydroxyurea induces fetal hemoglobin expression by activating cAMP signaling pathways in a cAMP- and cGMP-dependent mannerIkuta, 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.
Synergistic Enhancement of Sickle Red Blood Cell Adhesion to Endothelium by Hypoxia and Low Nitric Oxide BioavailabilityGutsaeva, 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.