Doxorubicin inhibits cholesterol efflux through the miR-33/ABCA1 pathway

Abstract

Doxorubicin (DOX) is extensively used for the treatment of kinds of cancers, and cardiovascular toxicity is one of the side effects. However, it is unclear whether DOX causes impairment of cardiac function by promoting atherosclerosis. Thus, we investigated the role of DOX in regulating the lipid deposition of macrophages and its molecular mechanism. RAW 264.7 cell line was stimulated with DOX in the presence or absence of low-density lipoprotein (LDL). We found that DOX increased miR-33 and reduced ATP binding cassette transporter A1 (ABCA1) protein. Moreover, cholesterol efflux was suppressed by DOX, which was more efficient under a high-cholesterol condition. After transfecting mimics or inhibitors of miR-33 into cells, ABCA1 protein was respectively decreased and increased, and intracellular lipid accumulation was correspondingly regulated. Overall, DOX suppresses the expression of ABCA1 protein by upregulating miR-33, promoting an intracellular lipid deposition in macrophages, which is a sign of early atherosclerosis. This provides new insights for clinical observation and evaluation of the side effects of DOX.

Keywords: ATP-Binding cassette transporter A1; Doxorubicin; Lipid deposition; Macrophage; microRNA-33.