Teniposide reduces vascular calcification by inhibiting BMP2 expression

Vascular calcification, characterized by ectopic calcium deposition, is clinically associated with the development of chronic kidney disease, atherosclerosis and diabetes mellitus. Bone morphogenetic proteins 2 (BMP2) regulates orthotopic bone formation physiologically. However, high expression of BMP2 in atherosclerotic lesions suggests that BMP2 may play an important role in vascular calcification under pathological conditions. Teniposide, a well‐defined DNA topoisomerase II (Topo II) inhibitor, is widely prescribed to patients with various types of cancers. In addition, we previously reported that teniposide is able to activate macrophage ABCA1 expression and free cholesterol efflux, and hepatic CETP expression indicating that Top II inhibitors may demonstrate multiple anti‐atherogenic properties. Herein, we investigated if teniposide can influence calcification in aortic root, and BMP2 is involved in this process. In vitro , we employed the β‐glycerophosphoric acid method to induce calcification in human aortic smooth muscle cells (HASMCs). We determined that treatment of HASMCs with teniposide attenuated the phosphate‐induced calcium deposition. Mechanistically, we found that teniposide suppressed HASMC calcification by decreasing the BMP2 and Smad1/5/8 signaling cascade in a p53‐dependent manner. To determine the effect of teniposide on vascular calcification, apoE deficient (apoE −/− ) mice were randomly divided into 3 groups and received the following treatment: Group 1 (control), mice were fed high‐fat diet (HFD) for 4 months; Group 2 (prevention group), mice were fed HFD containing teniposide [0.5 mg/kg bodyweight/day, (mpk)]; and Group 3 (therapy group) mice were pre‐fed with HFD alone for 3 months followed by one month of HFD containing teniposide (0.5 mpk). At the end of experiment, we determined the development of lesions and calcification. We observed that teniposide reduced atherosclerotic lesions and vascular calcification in lesion areas, in both prevention and therapy groups. The immunofluorescent staining demonstrates that BMP2 expression in the calcified vascular areas was also inhibited by teniposide. In contrast, the results of microCT analysis on the distal femur show no effect of teniposide on bone structure indicating the tissue‐type specific function of teniposide. Taken together, our study demonstrated that teniposide treatment ameliorates vascular calcification both in vitro and in vivo which was completed by regulating p53‐BMP2 pathway. Our study also demonstrates another biological function of TopII inhibitors. Support or Funding Information The National Science Foundation of China Grants 81473204 to J Han and 81573427 to Y Duan