Doxorubicin (DOX) is widely used as an anti-cancer agent although it causes irreversible cardiomyopathy
by increasing oxidative stress and deregulating nitric oxide production. Beraprost (BPS), a stable
prostacyclin (PGI2) analog, is a potent vasodilator that has beneficial effects on myocardial ischemia. The objectives of the
present study were to delineate the uncertain effects of prostcyclin therapy on DOX induced cardiomyopathy and to explore
the mechanisms underlying PGI2 and DOX interaction. For this reason, we stimulated endogenous PGI2 production
using bicistronic COX-1/PGIS gene transfer and BPS supplementation, and investigated the effects on DOX-induced cardiomyopathy.
Caspase-dependent protein content, lactate dehydrogenase (LDH), DNA fragmentation, and TUNEL positive
cells were elevated in DOX-treated cardiomyocytes. These indicators were further elevated by adenovirus-COX-
1/PGIS transfection or BPS supplementation. In addition, PGI2 overexpression further increased iNOS expression and superoxide
accumulation in cardiomyocytes compared with DOX alone, which may be the reason for aggravated cytotoxicity.
Moreover, BPS can induce cAMP response elements (CRE) binding to the iNOS promoter and phospho- cAMP response
element binding protein (CREB) expression in a cyclic AMP-dependent manner. Our in vivo studies show that
MnTBAP and aminoguanidine treatment of DOX and BPS co-administered in mice can attenuate caspase-3 and PARP-1
protein expression, and improve mouse survival, as observed in the iNOS gene-deleted mice. In conclusion, we demonstrated
that BPS or adv-COX-1/PGIS increases PGI2 levels through iNOS expression and peroxynitrite production, via
CREB protein phosphorylation; thereby aggravating DOX-mediated cardiotoxicity.