The program goal is to understand and limit ischemia-reperfusion injury in the elderly heat. Aging associated effects in mitochondrial electron transport result in increased generation of free radicals that propagate molecular, cellular, and tissue injury. Oxyradicals modify glutathione (GSH) and critical sylfhydryl groups on proteins that are vital for energy production, ion transport, gene regulation, membrane integrity, etc. The net effect of ischemia-reperfusion injuries is likely contributed by decrease in antioxidant protection and repair systems. The thiol-disulfide oxidoreductase (TDOR) enzymes thioltransferase and thioredoxin are important defense systems that maintain critical sulfhydryl proteins, yet they have not been featured in studies on aging, nor well characterized in mitochondria. This project is aimed at understanding age-related changes in protection and repair capacity of the TDOR enzymes, and at testing potential therapeutic agents that counteract the age-dependent changes. It is hypothesized that advanced age is associated with decline in capacity to protect viral sulfhydryl proteins, which could be due to diminution in contents of enzymes involved in sulfhydryl homeostasis or a decrease in the inducibility of these enzymes that is a natural part of the cellular response to oxidative stress. The primary focus will be cardiac myocytes, and mitochondria in particular. The primary animal model will be Fischer 344 rats. Specifically, this project will measure total and subcellular distribution of thioltransferase and thioredoxin contents and activities in heart tissues from 6, 18, 24 and 28 m.o. rats to determine changes in sulfhydryl protein defense capacity with aging and in response to ischemia- reperfusion, in the absence and presence of cell permeable antioxidant agents. The activities, thiol status, and nature of oxidative modification of key functional mitochondrial and cytosolic enzymes with sensitive sulfhydryl moieties will be studied to assess cytotoxic relevance of age- dependent changes in response to ischemia-reperfusion and antioxidant therapy. The same proteins will be studied in vitro to characterize the mechanism(s) of their oxidative modification and the relative efficiency of the thioltransferase and thioredoxin systems to catalyze repair. This study will provide new insights into protein-SH oxidation as a contribution mechanism of ischemia-reflow injury, and it will test the utility of cell-permeable antioxidants in mitigating that injury, especially in elderly animals that are more susceptible.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG015885-03
Application #
6359555
Study Section
Project Start
2000-09-30
Project End
2001-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$157,506
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Kim, Junhwan; Hoppel, Charles L (2013) Comprehensive approach to the quantitative analysis of mitochondrial phospholipids by HPLC-MS. J Chromatogr B Analyt Technol Biomed Life Sci 912:105-14
Solinas, Paola; Fujioka, Hisashi; Tandler, Bernard et al. (2012) Isolation of rat adrenocortical mitochondria. Biochem Biophys Res Commun 427:96-9
Xi, Lei; Zhu, Shu-Guang; Das, Anindita et al. (2012) Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications. Nitric Oxide 26:274-84

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