Inhibition of Vascular Calcification: A New Antiatherogenic Mechanism of Topo II (DNA Topoisomerase II) Inhibitors

Objective Vascular calcification is a major risk factor for rupture of atherosclerotic plaques. High expression of BMP2 (bone morphogenetic protein 2) in lesions suggests its importance in vascular calcification during atherosclerosis. Teniposide is a Topo II (DNA topoisomerase II) inhibitor and is used for cancer treatment. Previously, we reported that teniposide activated macrophage ABCA1 (ATP-binding cassette transporter A1) expression and free cholesterol efflux indicating Topo II inhibitors may demonstrate antiatherogenic properties. Herein, we investigated the effects of teniposide on the development of atherosclerosis and vascular calcification in apoE(-/-) (apoE deficient) mice. Approach and Results apoE(-/-) mice were fed high-fat diet containing teniposide for 16 weeks, or prefed high-fat diet for 12 weeks followed by high-fat diet containing teniposide for 4 weeks. Atherosclerosis and vascular calcification were determined. Human aortic smooth muscle cells were used to determine the mechanisms for teniposide-inhibited vascular calcification. Teniposide reduced atherosclerotic lesions. It also substantially reduced vascular calcification without affecting bone structure. Mechanistically, teniposide reduced vascular calcification by inactivating BMP2/(pi-Smad1/5/8 [mothers against decapentaplegic homolog 1, 5, and 8])/RUNX2 (runt-related transcription factor 2) axis in a p53-dependent manner. Furthermore, activated miR-203-3p by teniposide functioned as a link between activated p53 expression and inhibited BMP2 expression in inhibition of calcification. Conclusions Our study demonstrates that teniposide reduces vascular calcification by regulating p53-(miR-203-3p)-BMP2 signaling pathway, which contributes to the antiatherogenic properties of Topo II inhibitors.