Source: MICHIGAN STATE UNIV submitted to
INFLUENCE OF SELENOPROTEINS IN PROMOTING CARDIOVASCULAR HEALTH
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
TERMINATED
Funding Source
Reporting Frequency
Annual
Accession No.
0207265
Grant No.
2006-35200-17190
Project No.
MICL08383
Proposal No.
2006-01470
Multistate No.
(N/A)
Program Code
31.0
Project Start Date
Sep 1, 2006
Project End Date
Aug 31, 2010
Grant Year
2006
Project Director
Sordillo, L. M.
Recipient Organization
MICHIGAN STATE UNIV
(N/A)
EAST LANSING,MI 48824
Performing Department
LARGE ANIMAL CLINICAL SCIENCES
Non Technical Summary
Selenium is a trace mineral that has an essential role in maintaining human health and preventing cardiovascular disorders. The protective effects of selenium are thought to be mediated by several important selenoproteins, such as glutathione peroxidase. The goal of this project is to define which selenoproteins may protect the vascular endothelium from pro-oxidant challenge. The long-term implications of this work will be the ability to identify foods that can provide the optimal amount of specific biological active selenoproteins needed to control the development of atherosclerosis and other cardiovascular disorders.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
7015010101020%
7015010102010%
7015010103010%
7015010104010%
7025010101020%
7025010102010%
7025010103010%
7025010104010%
Goals / Objectives
The overall goal of this project is to fill the void of knowledge concerning the role of endothelial cell-derived selenoproteins in preventing vascular dysfunction. Studies are designed to determine which selenoproteins are capable of modifying cellular responses to oxidant challenge by controlling the balanced expression of cytoprotective and proapoptitic factors. The molecular pathways affected by altered selenoprotein activity will be identified. Further characterization of the role of selenoproteins in endothelial cell metabolism may provide new insights as to how Se may function as a nutraceutical and produce specific health benefits in combating cardiovascular disease.
Project Methods
In order to better understand the consequences of altered aortic vascular homeostasis during oxidant stress, we developed short interfering RNA constructs targeting both cytosolic and phospholipid hydroperoxide glutathione peroxidase. Effective knockdown of selenoprotein activity in transfected aortic endothelial cells mimics key events associated with vascular dysfunction during oxidant stress. Using these short interfering RNA constructs, we will determine the underlying molecular mechanisms responsible for the cytoprotective effects of endothelial cell-derived selenoproteins.

Progress 09/01/06 to 08/31/10

Outputs
OUTPUTS: Considerable evidence suggests an inverse relationship exists between selenium (Se) nutrition and cardiovascular disorders. The importance of Se to cardiovascular health may be related to the expression of a wide range of selenoproteins that have diverse biological roles. A unique model was used to fill the void of fundamental knowledge concerning the role of endothelial cell-derived selenoproteins in preventing vascular dysfunction. Several selenium-derived antioxidant enzymes were shown to prevent uncontrolled vascular inflammatory responses during pro-oxidant challenge. Selenium supplementation reduced adhesion molecule expression and leukocyte adhesion to endothelial cells. Furthermore, adhesion molecule expression increased proportionately when selenium-deficient endothelial cells were challenged with a pro-oxidant fatty acid hydroperoxide. Using techniques to silence the activity of individual selenoenzymes, the regulatory roles of glutathione peroxidase and thioredoxin reductase were identified in orchestrating the expression of either pro-inflammatory or cytoprotective genes necessary for cell survival during oxidant stress. PARTICIPANTS: Lorraine Sordillo served as the principal investigator for the project. She was involved with all aspects of the project including experimental design, conducting laboratory assays, analyzing data, interpretation of the findings, and preparing reports and manuscripts. Jeffery Gandy and Chris Corl were research technicians that contributed to the project. They conducted laboratory experiments in support of the project and assisted with manuscript preparation and reporting. Stacey Aitken was a graduate student pursuing a PhD degree. She received research training experience and developed scientific writing skills while working on various aspects of the project. Elizabeth Karcher was a postdoctoral research associate and she received research training while working on this project. TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
Despite the clear relationship between Se nutritional status and optimal health, the mechanisms responsible for the beneficial effects remain elusive. Oxidative stress is a contributing factor to several chronic diseases including atherosclerosis and selenium nutrition status is directly linked with oxidative stress. Results of this study provided important new fundamental information describing how endothelial-derived selenoproteins are involved in the regulation of vascular homeostasis during oxidant challenge. The underlying mechanisms involved in modifying endothelial responses were shown to be diverse with respect to different selenoproteins. A better understanding of the complex interplay of selenoproteins in regulating vascular functions will help to develop a rationale for promoting cardiovascular health by optimizing Se metabolites at specific tissue locations. The findings from this study is a significant first step in defining how the beneficial effects of selenium can be harnessed to combat chronic cardiovascular diseases, such as atherosclerosis.

Publications

  • Sordillo, L.M., Gandy, J.C., and Corl, C.M. 2009. Thioredoxin reductase attenuates vascular inflammatory responses during oxidative stress. Page 72 in Proc. 3rd International Immunonutrition Workshop, Girona, Spain.
  • Sordillo, L.M., Gandy, J.C., and Corl, C.M. 2009. Selenoproteins and vascular inflammatory responses during oxidative stress. Free Radic. Biol. Med. 47:S49-50.
  • Sordillo, L.M., J.C. Gandy, and C.M. Corl. 2010. Thioredoxin reductase attenuates vascular inflammatory responses during oxidative stress. Proc. Nutrition. Soc. 69:E317.
  • Sordillo, L.M., Corl, C.M. and Aitken, S.L. 2009. Role of selenium in vascular health and disease. Molecules. (submitted).


Progress 09/01/08 to 08/31/09

Outputs
OUTPUTS: Selenium is recognized as being fundamentally important to human health. Considerable evidence exists suggesting that low selenium intake can cause adverse health effects while supra-nutritional levels may provide added protection from disease through the actions of biologically active selenoenzymes. A unique model of vascular oxidative stress was developed based on selenium deficiency in bovine aortic endothelial cells (BAEC). We sought to determine whether certain selenium-derived antioxidant enzymes may contribute to uncontrolled inflammatory responses during pro-oxidant challenge. Selenium supplementation reduced adhesion molecule expression and leukocyte adhesion to BAEC. Furthermore, adhesion molecule expression increased proportionately when selenium-deficient BAEC were challenged with a pro-oxidant fatty acid hydroperoxide. Studies are underway to identify the specific selenoproteins that can facilitate these protective effects. PARTICIPANTS: Lorraine Sordillo served as the principal investigator for the project. She was involved with all aspects of the project including experimental design, conducting laboratory assays, analyzing data, interpretation of the findings, and preparing reports and manuscripts. Jeffery Gandy and Chris Corl were research technicians that contributed to the project. They conducted laboratory experiments in support of the project and assisted with manuscript preparation and reporting. Stacey Aitken was a graduate student pursuing a PhD degree. She received research training experience and developed scientific writing skills while working on various aspects of the project. Elizabeth Karcher was a postdoctoral research associate and she received research training while working on this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Despite the clear relationship between Se nutritional status and optimal health, the mechanisms responsible for the beneficial effects remain elusive. Results from this study will provide important new fundamental information describing how endothelial-derived selenoproteins are involved in the regulation of cellular homeostasis during oxidant challenge. It is likely that the underlying mechanisms are diverse and possibly differ between individual selenoproteins. A better understanding of the complex interplay of selenoproteins in regulating vascular functions will help to develop a rationale for promoting cardiovascular health by optimizing Se metabolites at specific tissue locations. The findings from this study would be a significant first step in defining how the beneficial effects of selenium can be harnessed to combat chronic cardiovascular diseases, such as atherosclerosis.

Publications

  • Sordillo, L.M., Corl, C.M. and Aitken, S.L. 2009. Role of selenium in vascular health and disease. Molecules. (submitted).
  • Sordillo, L.M., Gandy, J.C., and Corl, C.M. 2009. Selenoproteins and vascular inflammatory responses during oxidative stress. Free Radic. Biol. Med. 47:S49-50.
  • Sordillo, L.M., Corl, C.M. and Gandy, J.C. 2009. Thioredoxin reductase attenuates vascular inflammatory responses during oxidative stress. Proceedings of the Nutrition Society. (in press)


Progress 09/01/07 to 08/31/08

Outputs
OUTPUTS: Increased intercellular adhesion molecule 1 (ICAM-1) expression and enhanced leukocyte recruitment to the endothelium are critical steps in the early development of atherosclerosis. The establishment and resolution of vascular inflammatory responses, including the expression of adhesion molecules, can be regulated to a large extent by oxidative stress. Certain selenoproteins, such as thioredoxin reductase (TrxR1), possess important antioxidant defense functions in vascular endothelial cells that can counteract the damaging effects of oxidative stress. Using an oxidative stress model based on selenium deficiency in bovine aortic endothelial cells (BAEC), we sought to determine whether TrxR1 activity may contribute to the differential regulation of ICAM-1 during pro-oxidant challenge. Selenium supplementation reduced ICAM-1 expression and leukocyte adhesion to BAEC. Furthermore, ICAM-1 expression increased proportionately when selenium-deficient BAEC were challenged with a pro-oxidant fatty acid hydroperoxide. Subsequent results using TrxR1 siRNA showed that this selenoporotein is at least partially responsible for controlling ICAM1 expression during oxidative stress. Finally, restoring intracellular levels of the reduced substrate thioredoxin (Trx) in selenium-deficient BAEC was sufficient to reduce ICAM1 expression during oxidative stress. These data provide evidence for the involvement of the Trx/TrxR1 system in the regulation of ICAM1 expression in BAEC during pro-oxidant challenge. PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Se is recognized as being fundamentally important to human health. Considerable evidence exists suggesting that low Se intake can cause adverse health effects while supra-nutritional levels may provide added protection from disease. Despite the clear relationship between Se status and optimal health, the mechanisms responsible for the beneficial effects remain elusive. Results from this study will provide important new information describing how endothelial-derived selenoproteins are involved in the regulation of cellular homeostasis during oxidant challenge. It is likely that the underlying mechanisms are diverse and possibly differ between individual selenoproteins. A better understanding of the complex interplay of selenoproteins in regulating EC functions will help to develop a rationale for promoting cardiovascular health by optimizing Se metabolites at specific tissue locations. The findings from this study would be a significant first step in defining how the beneficial effects of Se can be harnessed to combat chronic cardiovascular diseases, such as atherosclerosis.

Publications

  • Sordillo, L.M., Streicher, K.L., Mullarky, I.K., Gandy, J.C., Trigona, W., and Corl, C.M. (2008). Selenium inhibits 15-hydroperoxyoctadecadienoic acid-induced intracellular adhesion molecule expression in aortic endothelial cells. Free Radic. Biol. Med. 44:34-43.
  • Sordillo, L.M. (2008) Selenium status and regulation of vascular homeostasis. Cell Biol. Toxicol. 24:S353-356.
  • Sordillo, L.M., Corl, C., and Gandy, J.C. (2008) Thioredoxin reductase attenuates vascular inflammatory responses during oxidative stress (abstract). in Proc. Experimental Biology Meetings. San Diego CA.
  • Sordillo, L.M., Gandy, J.C., Corl, C.M., and Aitken, S.L. (2008) Thioredoxin reductase attenuates vascular inflammatory responses during oxidative stress (abstract). Free Radic. Biol. Med. 45:S139.


Progress 09/01/06 to 08/31/07

Outputs
Certain selenoproteins such as glutathione peroxidase-1 (GPX-1) and thioredoxin reductase-1 (TrxR1) possess important antioxidant defense functions in vascular endothelial cells. Reduced selenoprotein activity during dietary selenium (Se) deficiency can result in a compensatory increase of other non-Se dependant antioxidants such as heme oxygenase-1 (HO-1) that may help to counteract the damaging effects of oxidant stress. However, the role of individual selenoproteins in regulating vascular-derived protective gene responses such as HO-1 is less understood. Using an oxidant stress model based on Se deficiency in bovine aortic endothelial cells (BAEC), we sought to determine whether TrxR1 activity may contribute to the differential regulation of HO-1 expression as a function of altered redox environment. Selenium sufficient BAEC upregulated HO-1 expression following stimulation with the pro-oxidant, 15-HPETE, and levels of this antioxidant inversely correlated with EC apoptosis. While -Se BAEC exhibited higher basal levels of HO-1, it was not upregulated upon 15-HPETE treatment which resulted in significantly higher levels of pro-apoptotic markers. Subsequent results showed that HO-1 induction depended on the activity of TrxR1, as proven with chemical inhibitor studies and direct inhibition with TrxR1 siRNA. Finally, restoring intracellular levels of the reduced substrate thioredoxin (Trx) in Se deficient BAEC was sufficient to increase HO-1 activation following 15-HPETE stimulation.

Impacts
The purpose of this work is to identify the mechanisms by which selenium nutrition can influence endothelial cell function. We provide evidence for the involvement of the selenium-dependent Trx/TrxR system in the regulation of vascular HO-1 expression during pro-oxidant challenge. These studies will lead to the development of effective ways to prevent vascular dysfunction and cardiovascular disease by modifying the selenium nutritional status of the host.

Publications

  • Trigona, W.L., Mullarky, I.K., Cao, Y., Sordillo, L.M. 2006. Thioredoxin reductase regulates the induction of haem oxygenase-1 expression in aortic endothelial cells. Biochemistry J. 394:207-216.