Inhibition of Vascular Calcification.

Abstract

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.

• Authors: Lipei Liu, Peng Zeng, Xiaoxiao Yang, Yajun Duan, Wenwen Zhang, Chuanrui Ma, Xiaomeng Zhang, Shu Yang, Xiaoju Li, Jie Yang, Yu Liang, Hao Han, Yan Zhu, Jihong Han, Yuanli Chen
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 38 Issue 10 Pg. 2382-2395 (10 2018) ISSN: 1524-4636 [Electronic] United States
• PMID: 30354214 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• BMP2 protein, human
• Bone Morphogenetic Protein 2
• Core Binding Factor Alpha 1 Subunit
• RUNX2 protein, human
• Smad Proteins
• TP53 protein, human
• Topoisomerase II Inhibitors
• Tumor Suppressor Protein p53
• Teniposide
• Alkaline Phosphatase

Topics

• 3' Untranslated Regions
• Alkaline Phosphatase (metabolism)
• Animals
• Aorta (drug effects, enzymology, pathology)
• Aortic Diseases (enzymology, genetics, pathology, prevention & control)
• Atherosclerosis (enzymology, genetics, pathology, prevention & control)
• Bone Morphogenetic Protein 2 (genetics, metabolism)
• Cells, Cultured
• Core Binding Factor Alpha 1 Subunit (genetics, metabolism)
• Disease Models, Animal
• Female
• Humans
• Mice, Knockout, ApoE
• Muscle, Smooth, Vascular (drug effects, enzymology, pathology)
• Myocytes, Smooth Muscle (drug effects, enzymology, pathology)
• Signal Transduction (drug effects)
• Smad Proteins (metabolism)
• Teniposide (pharmacology)
• Topoisomerase II Inhibitors (pharmacology)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Vascular Calcification (enzymology, genetics, pathology, prevention & control)