The olive constituent oleuropein prevents cardiac doxorubicin-induced changes in eNOS expression, apoptotic mediators and energy metabonomics in rats

Abstract

Purpose: Doxorubicin (DXR) causes cardiotoxicity through nitro-oxidative stress, but the exact pathogenesis is not fully elucidated. Oleuropein (OLEU), a polyphenolic constituent of olive and its products, prevents acute and chronic DXR-induced cardiotoxicity. We evaluated mechanisms potentially involved in chronic DXR cardiotoxicity, including eNOS, pro-apoptotic mediators and energy metabonomics as well as OLEU impact on these mechanisms. Methods: Ninety rats were divided into 6 groups: Control group, no treatment; OLEU-70 and OLEU-140 groups, 70 and 140 mg/kg of OLEU, respectively, given intraperitoneally (ip) for 2 weeks; DXR group, 18mg/kg of DXR ip, divided into 6 equal doses and given over a period of 2 weeks; OLEU-70-DXR and OLEU-140-DXR groups, combined OLEU and DXR as previously described. The rats were finally sacrificed and the hearts were excised for tissue assessment of eNOS, Akt and AMPK by immunohistochemistry and Western-Blot. NMR spectra of tissue extracts was also recorded and analyzed further by multivariate statistics. Results: DXR group had lower eNOS, Akt and AMPK activation compared to controls and all OLEU groups. The NMR-based metabonomic study depicted differences in the metabolic profile of DXR compared to all other groups (Figure) suggesting an impaired energy metabolism in this group and rehabilitation with OLEU administration. The inhibition of AMPK activation by DXR, correlated with the change in the profile of cardiac energy substrate utilization with a decrease in glucolysis and fatty acids oxidation. ![Figure][1] Conclusion: Impaired eNOS, Akt and AMPK expression and cardiac energy metabolism disruption is involved in chronic DXR cardiotoxicity; OLEU prevented those changes, thus providing a potential protective agent against DXR-induced cardiomyopathy. [1]: pending:yes