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Author Notes:

E-mail: soforia@emory.edu

Conceived and designed the experiments: SFOA.

Performed the experiments: FT SG OA YL.

Analyzed the data: TY SG YL SFOA.

Contributed reagents/materials/analysis tools: MM.

Wrote the paper: SFOA SG.

We are grateful to Dr. Townes of the University of Alabama, Birmingham for the knock-in transgenic mice with SCD, and to Dr. Archer of Emory University for the Berkeley mice.

We thank Dr. Mey Saied for assistance with image preparation, and Dr. Natalia Kozyr for assisting with analysis of the gene expression data.

The authors have declared that no competing interests exist.

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Research Funding:

This work was supported by National Institutes of Health (NIH) grant # K02HL088026 awarded to SFOA.

The gene expression studies were carried out in part with resources from the Emory Center for AIDS Research, NIH grant # P30-AI-50409.

The microarray study was supported by Emory's Clinical Research grant (CTSI grant # 1 UL1RR025008-03).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Global Gene Expression Profiling of Endothelium Exposed to Heme Reveals an Organ-Specific Induction of Cytoprotective Enzymes in Sickle Cell Disease

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Journal Title:

PLoS ONE

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Volume 6, Number 3

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Type of Work:

Article | Final Publisher PDF

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. Methods and Findings 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.

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© Ghosh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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