Abstract

The general aim of this research is to elucidate further the contribution of cytotoxic oxygen metabolites generated by the myocardium to ischemia/reperfusion-mediated damage. Much of the work focuses on adult myocardium; selected experiments assess differences between adult and neonatal myocardium in terms of oxidant contribution to damage. The experiments incorporate, where possible, correlative functional, biochemical, and morphologic approaches.
AIM 1 is to investigate with histochemistry and electron microscopy, the sites, pathways, and time-courses of oxidant (primarily H202) production. This helps test the fundamental hypothesis that H202 generated by the myocardium contributes to ischemic damage.
AIM 2 is to assess the activity of aldehyde exidase (AO) in nonischemic and ischemic-reperfused adult hearts. This enzyme may be a source of oxidants, and through its metabolism of malondialdehyde it could be a participant in a vicious cycle of oxidative damage to the ischemic heart.
AIM 3 is to assess biochemical mechanisms by which allopurinol acts in hearts that are allegedly devoid of its target enzyme, xanthine oxidase, either to produce beneficial or deleterious effects in the setting of ischemia.
AIM 4 is to assess the relative roles of catalase and glutathione peroxidase as pathways for degrading H202 in ischemic adult hearts. The overall significance is that a better understanding of pathophysiologic mechanisms will benefit future research on myocardial protection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029499-08
Application #
3340630
Study Section
Cardiovascular and Pulmonary Research B Study Section (CVB)
Project Start
1982-07-01
Project End
1993-09-29
Budget Start
1989-09-30
Budget End
1990-09-29
Support Year
8
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Mack, C P; Hultquist, D E; Shlafer, M (1995) Myocardial flavin reductase and riboflavin: a potential role in decreasing reoxygenation injury. Biochem Biophys Res Commun 212:35-40
Mack, C P; Brosamer, K M; Shlafer, M (1993) Ultrastructural demonstration of peroxidative activity and peroxidation in ischaemic and ischaemic-reperfused rabbit hearts. Cardiovasc Res 27:371-6
Xu, F; Mack, C P; Quandt, K S et al. (1993) Pyrroloquinoline quinone acts with flavin reductase to reduce ferryl myoglobin in vitro and protects isolated heart from re-oxygenation injury. Biochem Biophys Res Commun 193:434-9
Hultquist, D E; Xu, F; Quandt, K S et al. (1993) Evidence that NADPH-dependent methemoglobin reductase and administered riboflavin protect tissues from oxidative injury. Am J Hematol 42:13-8
Shlafer, M; Brosamer, K; Forder, J R et al. (1990) Cerium chloride as a histochemical marker of hydrogen peroxide in reperfused ischemic hearts. J Mol Cell Cardiol 22:83-97
Shlafer, M; Gallagher, K P; Adkins, S (1990) Hydrogen peroxide generation by mitochondria isolated from regionally ischemic and nonischemic dog myocardium. Basic Res Cardiol 85:318-29
Grum, C M; Gallagher, K P; Kirsh, M M et al. (1989) Absence of detectable xanthine oxidase in human myocardium. J Mol Cell Cardiol 21:263-7
Bove, E L; Gallagher, K P; Drake, D H et al. (1988) The effect of hypothermic ischemia on recovery of left ventricular function and preload reserve in the neonatal heart. J Thorac Cardiovasc Surg 95:814-8
Grum, C M; Ketai, L H; Myers, C L et al. (1987) Purine efflux after cardiac ischemia: relevance to allopurinol cardioprotection. Am J Physiol 252:H368-73
Shlafer, M; Myers, C L; Adkins, S (1987) Mitochondrial hydrogen peroxide generation and activities of glutathione peroxidase and superoxide dismutase following global ischemia. J Mol Cell Cardiol 19:1195-206

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