il\VOLVEMENT OF RETII\OIC ACID II{ - MSpace at the University of ...

apoptosis, which will ultimately progress in to heart failure. This hlpothesis was tested
using in vivo as well as in vitro studies.
For the in vivo studies, adriamycin induced heart failure was produced in rats
using a protocol previously established in our laboratory. Role of oxidative stress was
tested by treating the animals with the antioxidant, probucol. The changes in
hemodynamic function, body weight and general appearance of animals was observed
throughout the study. Total retinoic acid receptors (RAR and RXR) levels, specific
retinoic acid receptor subfamilies (u,B,y) levels, the expression of RXR heterodymeric
partner PPAR ô and changes in the pro and anti-apoptotic protein levels ( Bax and Bcl-xl)
were assessed at the late stage of adriamycin-induced heart failure.
In the in vitro studies, isolated adult cardiac myocytes were exposed to three
different concentrations of adriamycin (4, 8 and10 pM), with or without two different
concentrations of retinoic acid (0.1 and 1 pM) or antioxidant trolox (20 pM) for a period
of 8 hrs. Cells were then harvested and used for the measurement of all the parameters
analyzed in in vivo studies. The levels of oxidative stress and apoptosis were also
measured in these cells.
The data from this study has provided the evidence that: 1) Oxidative stress is
involved in the pathogeneses of adriamycin-induced apoptosis and this is achieved
through the increase in the RAR/RXR receptor ratio; 2) The oxidative stress-induced
increase in the RAR/RXR receptor ratio results in the upregulation of proapoptotic genes
which will lead to apoptosis in cardiac myocytes; 3) These changes can be prevented by
the administration of antioxidants (probucol and trolox) and low dose of retinoic acid
(0.1pM); 4) The administration of antioxidants and low dose of retinoic acid will result in