Project: Research project

Project Details


The main aim of this proposal is to elucidate the role of oxygen-
derived radicals (ODR) or cardiac injury during the calcium
paradox. A major hypothesis of this project is that during Ca++
depletion, the damage to myocytes is initiated by superoxide
radicals (O2-) and hydrogen peroxide (H2O2) generated in the
vascular endothelium. This damage is potentiated by hydroxyl
radical (OH-) production after reintroduction of Ca++. The injury
induced by O2-/H2O2 and OH- is not well known. Therefore, the
focus of the proposal will be investigate the roles of H2O2 alone,
or in combination with O2-, in causing injury to myocyte and
endothelial cells in culture, intact hearts, and cocultures of
myocytes and endothelial cells. Secondly, the roles of O2-/H2O2
and OH- in the induction of the CA++ paradox utilizing cultures of
myocytes and endothelial cells will be investigated. In this
manner, the potential contribution of endothelial cells in the
generation of O2-/H2O2 as initiating species in the pathogenesis
of Ca++ paradox will be investigated.

The above aims will be accomplished as follows: The cell injury
due to O2-/H2O2/OH- will be correlated with functional studies
including measuring contractility, enzyme release, lipid
peroxidation, altered distribution of Fe++ and quantitative cell
damage before and after specific interventions. Experiments
proposed utilizing endothelial cell and myocyte cultures will
permit us to study the direct effect of the individual O2-derived
species generated exogenously or during Ca++ depletion and Ca++
repletion, and the progressive stages in the development of Ca++
paradox. Superoxide and OH- generated during Ca++ depletion and
Ca++ repletion of cultured endothelial cells myocytes will be
identified and measured by cytochrome C assay and high pressure
liquid chromatography (HPLC). The use of HPLC for direct
measurement of OH- will be a unique and novel technique which will
enable us to define the role of OH- in myocyte injury. The
information derived from these studies will increase our
understanding of the fundamental mechanisms underlying the Ca++
paradox. Furthermore, the study will provide insight into the
development of new strategies to prevent the myocardial injury
which occurs during calcium-free cardioplegia, Ca++ paradox and
post-ischemic reperfusion.
StatusNot started


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