Genetic endothelial systems biology of sickle stroke risk

Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School, and Minneapolis Children's Hospital 55455, USA.
Blood (Impact Factor: 10.45). 05/2008; 111(7):3872-9. DOI: 10.1182/blood-2007-06-097188
Source: PubMed


Genetic differences in endothelial biology could underlie development of phenotypic heterogeneity among persons afflicted with vascular diseases. We obtained blood outgrowth endothelial cells from 20 subjects with sickle cell anemia (age, 4-19 years) shown to be either at-risk (n=11) or not-at-risk (n=9) for ischemic stroke because of, respectively, having or not having occlusive disease at the circle of Willis. Gene expression profiling identified no significant single gene differences between the 2 groups, as expected. However, analysis of Biological Systems Scores, using gene sets that were predetermined to survey each of 9 biologic systems, showed that only changes in inflammation signaling are characteristic of the at-risk subjects, as supported by multiple statistical approaches. Correspondingly, subsequent biologic testing showed significantly exaggerated RelA activation on the part of blood outgrowth endothelial cells from the at-risk subjects in response to stimulation with interleukin-1beta/tumor necrosis factoralpha. We conclude that the pathobiology of circle of Willis disease in the child with sickle cell anemia predominantly involves inflammation biology, which could reflect differences in genetically determined endothelial biology that account for differing host responses to inflammation.

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Available from: Robert P Hebbel, Nov 28, 2014
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    • "To date, systems biology high-throughput and large dataset methodologies, or “omics” studies, of SCD have included transcriptome analysis of blood outgrowth endothelial cells, monocytes and reticulocytes [45] in humans, and kidneys in transgenic sickle cell mice [46]. Blood outgrowth endothelial cell transcriptome analysis showed that individuals with SCD and arterial occlusion in the Circle of Willis had higher expression of genes regulated by NFK-B and RelA, regulators of inflammation [47]. Sickle cell monocytes demonstrated differential expression of genes involved in heme metabolism, cell-cycle regulation, antioxidant and stress responses, inflammation, and angiogenesis [48]. "
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    ABSTRACT: Current therapy for sickle cell disease (SCD) is limited to supportive treatment of complications, red blood cell transfusions, hydroxyurea, and stem cell transplantation. Difficulty in the translation of mechanistically based therapies may be the result of a reductionist approach focused on individual pathways, without having demonstrated their relative contribution to SCD complications. Many pathophysiologic processes in SCD are likely to interact simultaneously to contribute to acute vaso-occlusion or chronic vasculopathy. Applying concepts of systems biology and network medicine, models were developed to show relationships between the primary defect of sickle hemoglobin (Hb S) polymerization and the outcomes of acute pain and chronic vasculopathy. Pathophysiologic processes such as inflammation and oxidative stress are downstream by-products of Hb S polymerization, transduced through secondary pathways of hemolysis and vaso-occlusion. Pain, a common clinical trials endpoint, is also complex and may be influenced by factors outside of sickle cell polymerization and vascular occlusion. Future sickle cell research needs to better address the biologic complexity of both sickle cell disease and pain. The relevance of individual pathways to important sickle cell outcomes needs to be demonstrated in vivo before investing in expensive and labor-intensive clinical trials.
    Full-text · Article · Mar 2013 · The Scientific World Journal
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    • "Regarding endothelial biology specifically, we previously employed the present approach to reveal gene expression differences coincident with a corresponding exaggerated endothelial cell response to inflammation signaling among the subgroup of children with sickle cell anemia who develop arterial occlusive disease in the Circle of Willis at the base of the brain [37]. Similarly, the present study was enabled by the technology we previously devised [37] that allows production of robust cultures of reporter endothelial cells (BOEC, blood outgrowth endothelial cells) from peripheral blood obtained from specific, phenotypically-defined individuals, in the present case, those self-identified by race as being AA or CA. We chose this device for subject group assignment because it was the method used for seminal epidemiologic studies of stroke and hypertension prevalence among AA [2,3], and we wished the present results to be directly relevant to such studies. "
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    ABSTRACT: Health disparities and the high prevalence of cardiovascular disease continue to be perplexing worldwide health challenges. This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to the increased burden of cardiovascular disease and cancer among African Americans (AA) compared to Caucasian Americans (CA). From self-identified, healthy, 20 to 29-year-old AA (n = 21) and CA (n = 17), we established cultures of blood outgrowth endothelial cells (BOEC) and applied microarray profiling. BOEC have never been exposed to in vivo influences, and their gene expression reflects culture conditions (meticulously controlled) and donor genetics. Significance Analysis of Microarray identified differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey nine biological systems relevant to endothelial biology. At the highly stringent threshold of False Discovery Rate (FDR) = 0, 31 single genes were differentially expressed in AA. PSPH exhibited the greatest fold-change (AA > CA), but this was entirely accounted for by a homolog (PSPHL) hidden within the PSPH probe set. Among other significantly different genes were: for AA > CA, SOS1, AMFR, FGFR3; and for AA < CA, ARVCF, BIN3, EIF4B. Many more (221 transcripts for 204 genes) were differentially expressed at the less stringent threshold of FDR <.05. Using the biological systems approach, we identified shear response biology as being significantly different for AA versus CA, showing an apparent tonic increase of expression (AA > CA) for 46/157 genes within that system. Many of the genes implicated here have substantial roles in endothelial biology. Shear stress response, a critical regulator of endothelial function and vascular homeostasis, may be different between AA and CA. These results potentially have direct implications for the role of endothelial cells in vascular disease (hypertension, stroke) and cancer (via angiogenesis). Also, they are consistent with our over-arching hypothesis that genetic influences stemming from ancestral continent-of-origin could impact upon endothelial cell biology and thereby contribute to disparity of vascular-related disease burden among AA. The method used here could be productively employed to bridge the gap between information from structural genomics (for example, disease association) and cell function and pathophysiology.
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