title: The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice.
abstract: The vascular pathobiology of sickle cell anemia involves inflammation, coagulation, vascular stasis, reperfusion injury, iron-based oxidative biochemistry, deficient nitric oxide (NO) bioavailability, and red cell sickling. These disparate pathobiologies intersect and overlap, so it is probable that multimodality therapy will be necessary for this disease. We have, therefore, tested a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), for efficacy in reducing endothelial activation. We found that pulmonary vascular endothelial VCAM-1 and tissue factor (TF) expression (both are indicators of endothelial activation) are powerfully and significantly inhibited by TSA. This is seen both with pretreatment before the inducing stress of hypoxia/reoxygenation (NY1DD sickle transgenic mouse), and upon longer-term therapy after endothelial activation has already occurred (hBERK1 sickle mouse at ambient air). In addition, TSA prevented vascular stasis in sickle mice, it exhibited activity as an iron chelator, and it induced expression of the antisickling hemoglobin, hemoglobin F. Notably, the TSA analog SAHA (suberoylanilide hydroxaminc acid) that is already approved for human clinical use exhibits the same spectrum of biologic effects as TSA. We suggest that SAHA possibly could provide true, multimodality, salubrious effects for prevention and treatment of the chronic vasculopathy of sickle cell anemia.
authors.affiliation: Vascular Biology Center and the Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. hebbe001@umn.edu
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: Betty S
authors.initials: BS
authors.lastname: Pace
authors.forename: Anna N
authors.initials: AN
authors.lastname: Solovey
authors.forename: Rahn
authors.initials: R
authors.lastname: Kollander
authors.forename: Chine F
authors.initials: CF
authors.lastname: Abanonu
authors.forename: Julia
authors.initials: J
authors.lastname: Nguyen
authors.forename: Julie V
authors.initials: JV
authors.lastname: Vineyard
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.forename: Fuad
authors.initials: F
authors.lastname: Abdulla
authors.forename: Shadé
authors.initials: S
authors.lastname: Osifuye
authors.forename: John W
authors.initials: JW
authors.lastname: Eaton
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kelm
authors.forename: Arne
authors.initials: A
authors.lastname: Slungaard
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005319:Fetal Hemoglobin / Q000235:genetics; D006441:Hemoglobin A / Q000235:genetics; D006451:Hemoglobin, Sickle / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011667:Pulmonary Veins / Q000166:cytology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013925:Thromboplastin / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014699:Venules / Q000166:cytology / Q000502:physiology; D000077337:Vorinostat; D017086:beta-Thalassemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006451:Hemoglobin, Sickle; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007502:Iron Chelating Agents; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C012589:trichostatin A; D000077337:Vorinostat; D006441:Hemoglobin A; D005319:Fetal Hemoglobin; D013925:Thromboplastin