Global gene expression profiling of endothelium exposed to heme reveals an organ-specific induction of cytoprotective enzymes in sickle cell disease

• Published in: PloS one 2011-03, Vol.6 (3), p.e18399-e18399
• Main Authors: Ghosh, Samit, Tan, Fang, Yu, Tianwei, Li, Yuhua, Adisa, Olufolake, Mosunjac, Mario, Ofori-Acquah, Solomon F
• Format: Article
• Language: English
• Subjects: Analysis; Anemia, Sickle Cell - genetics; Anemia, Sickle Cell - metabolism; Animal models; Animals; Apoptosis; Arteriosclerosis; Atherosclerosis; Bioinformatics; Biology; Bladder cancer; Blood diseases; Breast cancer; Carotid arteries; Cell culture; Cells, Cultured; Cluster analysis; Data processing; Diabetes; DNA microarrays; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Endothelium - drug effects; Endothelium - metabolism; Enzymes; Esophagus; Experiments; Gene expression; Gene Expression Profiling - methods; Genes; Genetic engineering; Heme; Heme - pharmacology; Heme oxygenase (decyclizing); Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; Immunoblotting; Immunoglobulins; Immunohistochemistry; Ischemia; Lesions; Lung - metabolism; Lungs; Medical research; Medicine; Mice; Monomolecular films; Myocardium - metabolism; NAD; NAD(P)H Dehydrogenase (Quinone) - genetics; NAD(P)H Dehydrogenase (Quinone) - metabolism; NADPH quinone oxidoreductase; Occlusion; Oligonucleotide Array Sequence Analysis; Organs; Oxidoreductase; Oxygenase; Patients; Pediatrics; Polymerase Chain Reaction; Pulmonary arteries; Quinone oxidoreductase; Quinones; Reperfusion; Ribonucleic acid; RNA; Rodents; Sickle cell anemia; Sickle cell disease; System effectiveness; Tissues; Transgenic mice; Tumors; Veins & arteries
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0018399

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. 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. 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.