title: Global gene expression profiling of endothelium exposed to heme reveals an organ-specific induction of cytoprotective enzymes in sickle cell disease.
abstract: BACKGROUND
  Sickle cell disease (SCD) is characterized by hemolysis, vaso-occlusion and ischemia reperfusion injury. These events cause endothelial dysfunction and vasculopathies in multiple systems. However, the lack of atherosclerotic lesions has led to the idea that there are adaptive mechanisms that protect the endothelium from major vascular insults in SCD patients. The molecular bases for this phenomenon are poorly defined. This study was designed to identify the global profile of genes induced by heme in the endothelium, and assess expression of the heme-inducible cytoprotective enzymes in major organs impacted by SCD.
  
  
  RESULTS
  Total RNA isolated from heme-treated endothelial monolayers was screened with the Affymetrix U133 Plus 2.0 chip, and the microarray data analyzed using multiple bioinformatics software. Hierarchical cluster analysis of significantly differentially expressed genes successfully segregated heme and vehicle-treated endothelium. Validation studies showed that the induction of cytoprotective enzymes by heme was influenced by the origin of endothelial cells, the duration of treatment, as well as the magnitude of induction of individual enzymes. In agreement with these heterogeneities, we found that induction of two major Nrf2-regulated cytoprotective enzymes, heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1 is organ-specific in two transgenic mouse models of SCD. This data was confirmed in the endothelium of post-mortem lung tissues of SCD patients.
  
  
  CONCLUSIONS
  Individual organ systems induce unique profiles of cytoprotective enzymes to neutralize heme in SCD. Understanding this heterogeneity may help to develop effective therapies to manage vasculopathies of individual systems.
authors.affiliation: Aflac Cancer Center and Blood Disorders Service, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Samit
authors.initials: S
authors.lastname: Ghosh
authors.forename: Fang
authors.initials: F
authors.lastname: Tan
authors.forename: Tianwei
authors.initials: T
authors.lastname: Yu
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Li
authors.forename: Olufolake
authors.initials: O
authors.lastname: Adisa
authors.forename: Mario
authors.initials: M
authors.lastname: Mosunjac
authors.forename: Solomon F
authors.initials: SF
authors.lastname: Ofori-Acquah
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods*; D006418:Heme / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction
chemical_list: D006418:Heme; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse