Acute cardiotoxicity induced by doxorubicin in right ventricle is associated with increase of oxidative stress and apoptosis in rats.

Doxorubicin (DOX) is one of the most effective chemotherapeutic agents, but its efficiency is seriously limited by the risk of developing cardiomyopathy. The most recognized cardiotoxic effect is left ventricular (LF) dysfunction, but MRI and echocardiography data demonstrated significant right ventricle (RV) function impairment. In order to clarify this aspect, the present study investigated the potential of DOX to induce acute RV cardiotoxicity at the same time as LV impairment. Rats were intraperitoneally (i.p.) injected with a single dose of 15 mg/kg DOX. DOX-treated rats were characterized by decreased body and heart weights, elevated levels of creatine kinase (CK-MB) and lactate dehydrogenase (LDH) activities compared to controls. Biochemical analyses on RV tissue revealed that the level of malondialdehyde (MDA) was significant increased (p<0.05) and activities of catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPX) antioxidant enzymes were decreased by 13%, 27% and 18%, respectively, compared to control. Histopathogical and electron microscopic studies revealed DOX-induced damage in both ventricles and an increase of interstitial collagen fibers compared to controls (p<0.001), whereas immunohistochemical analysis showed weak and irregular desmin expression. Furthermore, mitochondrion-induced apoptotic pathways were also activated in both ventricles, as reflected by the up-regulation of Bax/Bcl-2 mRNA expression ratio (p<0.001) and increase of Bax and caspase-3 protein expression, as well as by the significant elevation of TUNEL positive nuclei, compared to controls (p<0.001). The results showed that DOX exerted RV toxic effects at the same time as those reported in the LV, which might be mediated through the mitochondrial-dependent apoptosis.

Chrysin attenuates cardiomyocyte apoptosis and loss of intermediate filaments in a mouse model of mitoxantrone cardiotoxicity.

Chrysin (CHR) is a natural flavonoid and is present in high concentration in honey, propolis and many plant extracts. The aim of the present study was to evaluate the effects of CHR to reduce cardiomyocyte apoptosis and loss of intermediate filaments in a mouse model of mitoxantrone cardiotoxicity. Morphology of the cardiomyocytes was determined by optic and transmission electron microscopy and biochemistry methods. The expression of Bcl-2, Bax and Caspase-3 were assessed by immunofluorecence. Tunel assay was used to assess apoptosis in cardiomyocytes. In addition, the distribution of desmin protein was evaluated using immunohistochemistry. Our results show that MTX treatment significantly increased serum levels of creatine kinase isoenzyme (CK-MB), indicator of cardiac injury and withdrawn under CHR protection. Expression levels of Bcl-2 decreased, while those of Bax and caspase-3 increased following MTX treatment. 50 mg/kg of daily CHR intake reduced Bax and caspase-3 immunopositivity and restored Bcl-2 levels to a value comparable to the control. TUNEL (+) cardiomyocyte nuclei of MTX group showed typical signs of apoptosis which almost completely disappeared in response to 50 mg/kg CHR treatment. In parallel, an irregular distribution and a weak expression of desmin is associated with MTX induced cardiotoxic effects which was also restored by CHR treatment. In conclusion chrysin inhibits MTX-triggered cardiomyocyte apoptosis via multiple pathways, including decrease of the Bax/Bcl-2 ratio and caspase-3 expression along with preservation of the desmin disarray.