Background: Imbalance in lipid metabolism and membrane lipid homeostasis has been observed in numerous diseases including heart failure and cardiotoxicity. Growing evidence links phospholipid alterations especially cardiolipins (CLs) to defects in mitochondrial function and energy metabolism in heart failure. We have shown recently that doxorubicin cardiotoxicity is more severe in male than female Wistar rats. We aimed to study whether this sex specificity is linked to differences in cardiac phospholipid profiles.
Results: Adult male and female rats were injected 2 mg/kg doxorubicin weekly for 7 weeks. Cardiac phospholipid molecular species were determined by liquid chromatography coupled with mass spectrometry fragmentation (LC)/MS(n). Sex difference in phosphatidylethanolamine and phosphatidylcholine species containing docosahexaenoic and docosapentaenoic acyl chains was observed, females having more than males. In both sexes, doxorubicin induced an important loss of the main CL(18:2)4, while the level of monolysocardiolipin MLCL(18:2)3 remained stable. However, a severe remodelling appeared in treated rats with the longest CL acyl chains in doxorubicin-treated females, which might compensate for the loss of tetra-linoleoyl CL. The level of oxidized cardiolipin was not particularly increased after doxorubicin treatment. Finally, expression of genes involved in the biosynthesis of fatty acid appeared to be decreased in doxorubicin-treated males.
Conclusions: These results emphasize for the first time the cardiac remodelling in the phospholipid classes after doxorubicin treatment. These observations suggest that doxorubicin has a sex-specific impact on the heart phospholipidome especially on cardiolipin, an essential mitochondrial lipid. Further studies are needed to better understand the roles of lipids in the anthracycline cardiotoxicity and sex differences, but phospholipid cardioprotection seems a valuable new additive therapeutic strategy for anthracycline cardiotoxicity.
Keywords: Cardiolipin; Doxorubicin; Heart failure; LC/MSn; Sex-specific.