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Cortistatin inhibits calcification of vascular smooth muscle cells by depressing osteoblastic differentiation and endoplasmic reticulum stress

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Abstract

Accumulating evidence has indicated that vascular smooth muscular cells (VSMCs) play an important role in the development of vascular calcification (VC). Cortistatin (CST), a novel bio-active peptide, has been shown to exert multiple protective effects on the cardiovascular system. However, the role and possible mechanism of CST in VC remain unclear. Therefore, we used β-glycerophosphoric acid (β-GP) to induce calcification in rat and human VSMCs to determine the effects of CST on osteoblastic differentiation and VSMC mineralization in vitro. Compared with the control, β-GP significantly increased alkaline phosphatase (ALP) activity and calcium content in cultured rat and human VSMCs, as well as multicellular node formation and calcium deposition, as confirmed by von Kossa and Alizarin Red S staining assays. After incubating rat and human VSMCs with β-GP in the presence of different doses of CST (10−8 or 10−7 mol/L), CST clearly reversed the β-GP-induced increases in ALP activity and calcium content and formation of pathological calcified nodes of VSMCs in a dose-independent manner. Moreover, 10−8 and 10−7 mol/L CST inhibited the phenotypic transformation of VSMCs into osteoblastic cells by decreasing the osteocalcin protein levels, increasing the SM-α-actin protein levels, and reducing endoplasmic reticulum stress by decreasing the protein expression of glucose-regulated protein 94 and CCAAT/enhancer-binding protein homologous protein. In conclusion, CST directly inhibited β-GP-induced calcification of VSMCs in vitro, probably by suppressing ERS and phenotypic transformation of VSMCs into osteoblastic cells. These results indicate that CST represents a potential target for the prevention and treatment of VC.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (Grant Nos. 81200235 and 81200143), Research Foundation of Education Bureau of Heilongjiang Province, China (Grant No. 12541338) and Foundation of the First Affiliated Hospital of Harbin Medical University, Harbin, China (Grant No. 2015B005). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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    1. Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, NanGang District, Harbin, 150001, Heilongjiang, China

      Yue Liu, Fang Lin, Yu Fu, Wenjia Chen, Wenxiu Liu, Jinyu Chi, Xiaohui Zhang & Xinhua Yin

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    1. Yue Liu
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    2. Fang Lin
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    Handling Editor: T. Langer.

    Y. Liu and F. Lin contributed equally to this work.

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    Liu, Y., Lin, F., Fu, Y. et al. Cortistatin inhibits calcification of vascular smooth muscle cells by depressing osteoblastic differentiation and endoplasmic reticulum stress. Amino Acids 48, 2671–2681 (2016). https://doi.org/10.1007/s00726-016-2303-3

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