Abstract
BackgroundImbalance 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.ResultsAdult 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)/MSn. 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-015-0039-5) contains supplementary material, which is available to authorized users.
Highlights
Imbalance in lipid metabolism and membrane lipid homeostasis has been observed in numerous diseases including heart failure and cardiotoxicity
We have recently observed that after 7 weeks of doxorubicin treatment, male rats but not females had high mortality rate, signs of heart failure, and altered mitochondrial function, and we identified a significant decrease in total cardiolipin content in the heart of treated males [5]
We have shown recently that males were less protected against DOXO cardiotoxicity and that cardiolipin content was differently altered in males and females under DOXO
Summary
Imbalance in lipid metabolism and membrane lipid homeostasis has been observed in numerous diseases including heart failure and cardiotoxicity. Doxorubicin (DOXO), a widespread anti-cancer agent, has clinical limited use due to important deleterious cardiac side effects that lead to heart failure (HF). How anthracyclines induce both anti-cancer activity and cardiotoxicity are not completely understood [1]. Cardiolipin, a signature PL of the inner membrane of the mitochondria (around 20 % of the lipid composition), is involved in numerous functional and structural features of membrane-bound mitochondrial proteins and is linked to important mitochondrial processes, including apoptosis, mitochondrial dynamics, contact sites formation and assembly, and function of mitochondrial membrane proteins for an effective oxidative phosphorylation (reviewed in [9,10,11,12]). Alteration in CL content and composition has been associated with numerous disorders like diabetes, thyroid status, aging, and heart failure [14]
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