Our long-term goal is to develop a strategy to decrease the excess myocardial injury in elderly patients following an acute myocardial infarction. We have developed an approach to study this problem in the elderly Fischer 344 rat model. The isolated, buffer perfused elderly heart sustains greater injury after ischemia and reperfusion compared to the adult heart. At baseline, aging-defects in the mitochondrial electron transport chain occurs in only one population of heat mitochondria (interfibrillar) in elderly Fischer 344 rats. Following ischemia there is further damage to the interfibrillar mitochondria. We propose that aging- related defects in mitochondrial oxidative metabolism present at baseline in the elderly heart predispose to a subsequent increase in oxidative injury during ischemia and reperfusion compared to the adult heart, and that an excess of oxidative damage accounts for the increase in injury observed in the aging heart. The five interactive projects herein will use interventions that are designed to reduce the excess injury in the aging heat as tools to establish and intracellular sites of the increased damage that occurs in the aging heart during ischemia and reperfusion. We will test the hypothesis that the increase in Tumor Necrosis Factor alpha observed in aging tissue to the aging-related defect in complex II in interfibrillar mitochondria in the aging heart. We will determine if therapeutic intervention with a cell-permeable antioxidant N-2- mercaptopropionylglycine will protect the aging heart against the excess injury that occurs during ischemia and reperfusion, and will challenge the hypothesis that the tandem ischemic and aging-related defects in complex III in interfibrillar mitochondria increases damage in the aging heart via oxidative mechanisms. We will determine this structural basis of the ischemic defect in the Rieske iron-sulfur protein in complex III in interfibrillar mitochondria, and if the iron-sulfur protein sustains additional oxidative damage during reperfusion. We will test the hypothesis that oxidative damage to the enzyme carnitine palmitoyltransferase-I, the rate limiting step in fatty acid oxidation, occurs in interfibrillar mitochondria and leads to inappropriately increased fatty acid-oxidation and the accompanying deleterious consequences of excess fatty acid oxidation during reperfusion. We will challenge the hypothesis that a decrease in antioxidant defense mechanisms, including thioltransferase, in the aging heart results in increased oxidative injury.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG015885-04
Application #
6372236
Study Section
Special Emphasis Panel (ZAG1-PKN-2 (M3))
Program Officer
Kohanski, Ronald A
Project Start
1998-08-15
Project End
2004-07-31
Budget Start
2001-09-30
Budget End
2004-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$802,394
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Minkler, Paul E; Stoll, Maria S K; Ingalls, Stephen T et al. (2015) Quantitative acylcarnitine determination by UHPLC-MS/MS--Going beyond tandem MS acylcarnitine ""profiles"". Mol Genet Metab 116:231-41
Xu, Aijun; Szczepanek, Karol; Maceyka, Michael W et al. (2014) Transient complex I inhibition at the onset of reperfusion by extracellular acidification decreases cardiac injury. Am J Physiol Cell Physiol 306:C1142-53
Dadabayev, Alisher R; Yin, Guotian; Latchoumycandane, Calivarathan et al. (2014) Apolipoprotein A1 regulates coenzyme Q10 absorption, mitochondrial function, and infarct size in a mouse model of myocardial infarction. J Nutr 144:1030-6
Kerner, Janos; Minkler, Paul E; Lesnefsky, Edward J et al. (2014) Fatty acid chain elongation in palmitate-perfused working rat heart: mitochondrial acetyl-CoA is the source of two-carbon units for chain elongation. J Biol Chem 289:10223-34
Solinas, Paola; Fujioka, Hisashi; Radivoyevitch, Tomas et al. (2014) Aging effects on oxidative phosphorylation in rat adrenocortical mitochondria. Mech Ageing Dev 138:10-4
Gao, Xing-Huang; Qanungo, Suparna; Pai, Harish V et al. (2013) Aging-dependent changes in rat heart mitochondrial glutaredoxins--Implications for redox regulation. Redox Biol 1:586-98
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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