Abstract

The mechanism of iron-mediated myocardial injury by reactive oxygen metabolites will be studied in cultured cardiac myocytes, isolated rabbit hearts and intact dogs. Cultured myocytes will be exposed to oxygen metabolites or activated neutrophils and the time course of membrane injury (determined by leakage of enzymes or radiolabeled chromium), production of hydroxyl radical (detected by spin trapping), and appearance of myocardial lipid peroxides (by direct measurement) will be determined. The effect of reduced iron availability through iron chelation, alterations in intracellular pH or downregulation of transferrin receptors on myocardial injury will be studied. The efficacy of highly permeable scavengers of reactive oxygen metabolites, membrane protective agents, and infusion of a sulfhydryl donor in preventing myocardial injury, inhibiting lipid peroxidation, and avoiding depletion of sulfhydryl groups will be examined in cultured myocytes, isolated hearts or intact canine models exposed to potential oxidant injury.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048177-03
Application #
2224236
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1992-05-01
Project End
1996-04-30
Budget Start
1994-05-01
Budget End
1996-04-30
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Keller, M; Kong, Y; Robertson, A D et al. (1997) Prevention of coronary vascular abnormalities early in reperfusion with TGF-beta may not prevent late coronary vascular injury. J Cardiovasc Pharmacol 30:197-204
Horwitz, L D; Kaufman, D; Kong, Y (1997) An antibody to leukocyte integrins attenuates coronary vascular injury due to ischemia and reperfusion in dogs. Am J Physiol 272:H618-24
Gill, E A; Kong, Y; Horwitz, L D (1996) An oligosaccharide sialyl-Lewis(x) analogue does not reduce myocardial infarct size after ischemia and reperfusion in dogs. Circulation 94:542-6
Horwitz, L D; Wallner, J S; Decker, D E et al. (1996) Efficacy of lipid soluble, membrane-protective agents against hydrogen peroxide cytotoxicity in cardiac myocytes. Free Radic Biol Med 21:743-53
Horwitz, L D; Leff, J A (1995) Catalase and hydrogen peroxide cytotoxicity in cultured cardiac myocytes. J Mol Cell Cardiol 27:909-15
Crowley, S T; Ray, C J; Nawaz, D et al. (1995) Multiple growth factors are released from mechanically injured vascular smooth muscle cells. Am J Physiol 269:H1641-7
Byler, R M; Sherman, N A; Wallner, J S et al. (1994) Hydrogen peroxide cytotoxicity in cultured cardiac myocytes is iron dependent. Am J Physiol 266:H121-7
Kong, Y; Lesnefsky, E J; Ye, J et al. (1994) Prevention of lipid peroxidation does not prevent oxidant-induced myocardial contractile dysfunction. Am J Physiol 267:H2371-7
Horwitz, L D; Fennessey, P V; Shikes, R H et al. (1994) Marked reduction in myocardial infarct size due to prolonged infusion of an antioxidant during reperfusion. Circulation 89:1792-801
Horwitz, L D; Kaufman, D; Keller, M W et al. (1994) Time course of coronary endothelial healing after injury due to ischemia and reperfusion. Circulation 90:2439-47

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