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

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 pres-ence 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.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

Doxorubicin (DOX) is used for cancer treatment but can cause cardiovascular toxicity. This study examined whether DOX promotes atherosclerosis by impairing cardiac function. The results showed that DOX increased miR-33 expression and reduced the protein level of ATP binding cassette transporter A1 (ABCA1). DOX also suppressed cholesterol efflux, especially under high-cholesterol conditions. Transfection of miR-33 mimics or inhibitors into cells respectively decreased or increased ABCA1 protein expression and regulated intracellular lipid accumulation. Overall, DOX upregulates miR-33 to suppress ABCA1 expression, leading to intracellular lipid deposition in macrophages, which is an early sign of atherosclerosis. This study provides new insights for the clinical observation and evaluation of DOX side effects.