Prior exposure to doxorubicin exacerbates atherosclerotic plaque formation in apolipoprotein-E-deficient mice on a high-fat diet

Abstract

Background and aims

Epidemiological data suggest that anthracyclines, such as doxorubicin (DOX), promote atherosclerosis in cancer survivors. However, this has not been established experimentally so far. Here, we investigated whether DOX pre-exposure exacerbates atherosclerotic plaque formation (Study 1) as well as the impact of DOX on plaque progression (Study 2). Further, we evaluated the role of alpha-1-antichymotrypsin (Serpina3n) and thrombospondin-1 (Thbs1) in these plaques as we previously identified these proteins to be associated with DOX-induced cardiovascular disease.

Methods

In Study 1, DOX (4 mg/kg body weight/week) was administered for three weeks to apolipoprotein-E-deficient mice followed by a high-fat plaque-promoting diet for 8 weeks. In Study 2, mice were fed a high-fat diet for 17 weeks with DOX administered concomitantly from the third week of diet for three weeks. Plaque size and composition were assessed in the thoracic aorta, brachiocephalic artery and proximal ascending aorta.

Results

Prior DOX exposure increased plaque size along the aortic tree, regardless of sex. This was accompanied by enhanced cell death (increased TUNEL positivity) as well as elevated Serpina3n and Thbs1 in plaques of DOX-treated mice. DOX did not change total cholesterol, HDL and LDL plasma concentrations. Conversely, concomitant DOX exposure did not enhance plaque size nor affect overall plaque composition along the aortic tree, highlighting the importance of experimental design.

Conclusions

Early DOX exposure exacerbated plaque development in mice, providing first experimental evidence for anthracycline chemotherapy as a possible risk factor for atherosclerosis in cancer patients.