title: Evolution of novel small-molecule therapeutics targeting sickle cell vasculopathy.
abstract: A 34-year-old African American woman with sickle cell disease and history of relatively severe hemolysis, chronic leg ulcers, and mild pulmonary hypertension presented with a new ischemic stroke. Recent research has suggested a syndrome of hemolysis-associated vasculopathy in patients with sickle cell disease, which features severe hemolytic anemia and leads to scavenging of nitric oxide and its biochemical precursor l-arginine. This diminished bioavailability of nitric oxide promotes a hemolysis-vascular dysfunction syndrome, which includes pulmonary hypertension, cutaneous leg ulceration, priapism, and ischemic stroke. Additional correlates of this vasculopathy include activation of endothelial cell adhesion molecules, platelets, and the vascular protectant hemeoxygenase-1. Some known risk factors for atherosclerosis are also associated with sickle cell vasculopathy, including low levels of apolipoprotein AI and high levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase. Identification of dysregulated vascular biology pathways in sickle vasculopathy has provided a focus for new clinical trials for therapeutic intervention, including inhaled nitric oxide, sodium nitrite, L-arginine, phosphodiesterase-5 inhibitors, niacin, inhaled carbon monoxide, and endothelin receptor antagonists. This article reviews the pathophysiology of sickle vasculopathy and the results of preliminary clinical trials of novel small-molecule therapeutics directed at abnormal vascular biology in patients with sickle cell disease.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, 10 Center Dr, MSC 1476, Bldg 10-CRC, Room 5-5140, Bethesda, MD 20892-1476, USA. gkato@mail.nih.gov
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kato
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000150:complications / Q000503:physiopathology* / Q000628:therapy*; D001053:Apolipoproteins / Q000378:metabolism; D001119:Arginase / Q000378:metabolism; D001792:Blood Platelets / Q000502:physiology; D002986:Clinical Trials as Topic; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D016166:Free Radical Scavengers; D006419:Heme Oxygenase (Decyclizing); D006451:Hemoglobin, Sickle / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006976:Hypertension, Pulmonary / Q000209:etiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007871:Leg Ulcer / Q000209:etiology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D020521:Stroke / Q000209:etiology; D014652:Vascular Diseases / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy*; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D001053:Apolipoproteins; D016166:Free Radical Scavengers; D006451:Hemoglobin, Sickle; D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D001119:Arginase