ISCHEMIC HEART INJURY--MODIFICATION BY DRUG THERAPY

Project: Research project

Project Details

Description

The overall goal of this project is to understand the role of oxygen
derived radical (ODR) on cardiac injury during ischemia and postischemic
injury. A major focus of the current proposal is to understand the role
of hydroxyl radical (OH) and singlet oxygen (O2) in the pathogenesis of
ischemic injury and their effect on adenosine-mediated protection in the
ischemic heart. We are proposing that (1) both OH and O2 are generated
during postischemic in the reperfusion and that O2 is much more toxic
than OH. We will directly investigate O2 production during postischemic
reperfusion with electron paramagnetic spin resonance spectroscopy (EPR)
and HPLC, correlate it with resultant injury quantitatively and study the
intracellular mechanisms leading to O2 formation from H2O2 or OH. We
also propose that isolated myocytes and endothelial cells (EC) produce
OH and O2 during post-anoxic reoxygenation and this production is
primarily linked to metabolic abnormalities and the resumption of
mitochondrial respiration. Finally, the contribution of endothelial
cells towards ischemic injury to myocytes will be investigated with the
coculture of EC and myocytes. The second major emphasis is on the role
of adenosine in protection against I/R. It is proposed that adenosine
and its analogs inhibit ODR generation via receptor-mediated mechanisms.
Oxygen-derived radicals inhibit the nucleotidase activity and adenosine
production which has deleterious effect on cell viability during I/R.
We further plan to test the hypothesis that ischemic myocytes release
various nucleosides which are catabolized by EC xanthine oxidase
resulting in ODR injuries to myocytes. This will be done in both
isolated hearts and coculture of myocytes and endothelial cells.
Experiments proposed utilizing isolated cultured myocytes and EC will
allow us to study the direct effect of OH and O2 and progressive stages
in the process of cell death and their effect on the adenosine-mediated
cardioprotection. Direct knowledge of ischemic cell injury caused by OH
and O2 and their harmful effect on adenosine-mediated beneficial actions
will be important in the development of new improved strategies to retard
or prevent myocardial injury in man.
StatusNot started