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Intramural Papers of the Month

By Robin Arnette
April 2008

Hormones Can Affect the Expression of Cardiac Genes

Researchers from NIEHS and the National Heart, Lung, and Blood Institute (NHLBI) determined that the gene for lipoprotein lipase (LPL), an enzyme that hydrolyzes lipids in lipoproteins, is regulated by estrogen in cardiac tissue. The study was funded by the NIH Intramural Program and published in a recent issue of Endocrinology.

Earlier studies had demonstrated that estrogen, acting through the estrogen receptor beta (ERβ), had a protective effect on the heart. In this research article, the research team extended its studies to show that estrogen had direct effects on gene regulation in the heart. Team members treated heart tissue from ovarviectomized female mice with estrogen or vehicle (control) for two hours. Team members froze the hearts, isolated RNA and measured LPL expression using real-time PCR. The estrogen-exposed hearts exhibited a significant increase in LPL mRNA, but this stimulation could be inhibited by the addition of progesterone or an estrogen receptor antagonist.

Sequence analysis of the LPL gene indicated that an estrogen response element possibly existed in the first intron. Further studies indicated that ER? and ER? interacted strongly with the proposed sequence.

LPL is an essential regulator of fatty acid uptake in the heart, and altered LPL expression, due to the influence of estrogen and progesterone, could lead to cardiac malfunction. These studies provide valuable information on the role that hormones play in gene regulation.

Citation:Liu, D, Deschamps A, Korach KS, Murphy E( Exit NIEHS Website. Estrogen-enhanced gene expression of lipoprotein lipase in heart is antagonized by progesterone. Endocrinology 2008 Feb;149(2):711-716.

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Singlet Oxygen Production Indicates Site of Irradiation Damage

Cellular proteins are often damaged after a cell has been irradiated with UV or visible light, and scientists may use one of the mediators of this damage, singlet oxygen, to indicate which parts of the cell were affected. That's according to NIEHS researchers who published their results in Photochemistry and Photobiology. The work was supported by the NIH Intramural Program.

In earlier studies, the group had irradiated rose bengal (RB)-stained keratinocytes using visible light and had successfully detected singlet oxygen, but it was unable to determine exactly where the singlet oxygen had been produced in the cells. Therefore, the team tried again, this time using immuno-spin trapping to visualize the site.

The experiment involved the following reactions. When cells are exposed to singlet oxygen-generating dyes such as RB, protein hydroperoxides (POOH) are produced. In the presence of metal ions such as copper, POOH is converted to POO• and PO•, which both react with 5,5-dimethyl-1-pyrroline N-oxide (DMPO), a nitrone widely used in spin trap detection of free radicals. The keratinocytes were stained with DMPO antibody and a fluorescently-tagged anti-rabbit IgG and subjected to confocal microscopy. The results indicated that the singlet oxygen was being produced around the nucleus.

This work provides specific knowledge about the distribution of singlet oxygen, and therefore, damage after irradiation.

Citation: He Y-Y, Council SE, Feng, L, Bonini MG, Chignell CF( Exit NIEHS Website. Spatial distribution of protein damage by singlet oxygen in keratinocytes. Photochem Photobiol 2008 Jan-Feb;84(1):69-74.

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Cell Surface Receptor Involved in Innate Immune Response

In an article published in The FASEB Journal, researchers from NIEHS and Harvard University reported that scavenger receptor class-A (SR-A), one of the eight subclasses of scavenger receptors, is responsible for binding viral double-stranded RNA (dsRNA) and initiating cellular pathways involved in innate immune response. The work was funded by the NIEHS Intramural Research Program.

Prior to this report, scientists knew that dsRNA induced signal transduction pathways inside the cell, such as NF-?B and MAPK, which led to the regulation of inflammatory cytokines. However, they didn't know how it was done. Team members radiolabelled polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA that is used to model viral infections in vivo, and used it in competition assays. The results indicated that poly I:C competitively bound to SR-A. In addition SR-A antibodies and ligands inhibited internalization of poly I:C into cells.

This study indicates that SR-A is a novel receptor on the surface of lung epithelial cells that participates in innate immunity. The findings suggest that eventually researchers may be able to develop new therapeutics that will target the receptor and prevent viral infection.

Citation: Limmon GV, Arredouani M, McCann KL, Corn Minor RA, Kobzik L, Imani F( Exit NIEHS Website. Scavenger receptor class-A is a novel cell surface receptor for double-stranded RNA. FASEB J 2008 Jan;22(1):159-157.

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Silicone Implants, Connective Tissue Disease and Monoclonal Gammopathies

The results of a case-control study determined that silicone implants pose no increased risk of monoclonal gammopathies to women. The work, published in Arthritis Research & Therapy, was carried out by researchers from NIEHS, the NIH Clinical Center, the University of Michigan Medical School and the University of Utah Medical Center. The project was funded by the FDA Office of Women's Health and the Intramural Programs of the NIH (Clinical Center and NIEHS).

Previous studies had suggested a link between the appearance of abnormal serum proteins, including monoclonal gammopathies, also called paraproteins, in women with silicone breast implants. However, these investigations did not take into account the presence of connective-tissue disease (CTD). To address the issue, the team studied several groups of women at tertiary-care academic centers and performed serum protein determinations and immunofixation electrophoresis on the women's blood to detect monoclonal gammopathies.

Team members determined that women with implants, either with or without CTD, had lower serum globulin and immunoglobulin levels than women without implants, but overall there was no increased risk of paraproteinemia for women with implants. This study represents the first comprehensive study of serum proteins in women with silicone implants and CTD.

Citation: Csako G, Costello R, Shamim EA, O'Hanlon TP, Tran A, Clauw DJ, Williams HJ, Miller FW( Exit NIEHS Website. Serum proteins and paraproteins in women with silicone implants and connective tissue disease: a case-control study. Arthritis Res Ther 2007 9(5):R95.

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