MYOCARDIAL ISCHEMIC INJURY: MODIFICATION BY DRUG THERAPY

Project: Research project

Project Details

Description

The goal of this project is to understand the role of oxygen-
derived radicals on cardiac cell injury during ischemia and post-
ischemic reperfusion. Mechanisms and characteristics of cell
injury by hydrogen peroxide (H2O2), superoxide (O2) and hydroxyl
(OH.) radicals exposure in myocyte cultures and intact
myocardium will be investigated. In addition, in order to further
investigate the cell injury, sites of O2 and OH. production in
myocytes will be studied. A major focus of the current proposal is to understand the role
hydrogen peroxide and hydroxyl radical play in the pathogenesis of
ischemia mediated cardiac cell injury. We are proposing that (1)
H2O2 is one of important O2 metabolites in causing injury to
myocytes through OH. production and lipid peroxidation. Since
the generation of H2O2 is closely linked with O2, the damage by
individual metabolites in the cell injury is not known. We will
concentrate our efforts on understanding the role H2O2 (alone or
in combination with O2) plays in cell damage; (2) we will directly
investigate the OH. production during post-ischemic reperfusion,
correlate it with resultant injury quantitatively and study the
intracellular mechanism leading to OH. formation from H2O2.
We also propose to demonstrate that myocytes produce O2/OH.
during post-anoxic reoxygenation, and this production is primarily
linked to metabolic abnormalities and the reperfusion of
mitochondrial respiration. Superoxide and OH. generated in both hearts and myocytes will be
directly identified and measured by cytochrome C assay and high
pressure liquid chromatography. The cell injury will be correlated
with heart function, altered biochemistry and quantitative cell
damage before and after therapeutic interventions. Experiments
proposed utilizing isolated cultured myocytes will allow us to
study the direct effect of specific oxygen radical species and the
progressive stages in the process of cell death as will be
visualized by microscopic markers. Direct knowledge of ischemic
cell injury caused by specific oxygen-derived radicals will be
important in the development of new improved palliative
strategies to retard or prevent myocardial injury in man.
StatusNot started