Full Text | PDF

Theranostics 2021; 11(3):1129-1146. doi:10.7150/thno.49771 This issue Cite

Research Paper

ERK1/2 inhibition reduces vascular calcification by activating miR-126-3p-DKK1/LRP6 pathway

Peng Zeng^1*, Jie Yang^1*, Lipei Liu¹, Xiaoxiao Yang², Zhi Yao³, Chuanrui Ma⁴, Haibo Zhu⁵, Jiamin Su², Qian Zhao², Ke Feng¹, Shu Yang¹, Yan Zhu⁶, Xiaoju Li¹, Wenguang Wang⁷, Yajun Duan², Jihong Han^1,2✉, Yuanli Chen^2✉

1. College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
2. Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, China.
3. Tianjin Medical University, Tianjin, China.
4. First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
5. Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
6. Tianjin University of Traditional Chinese Medicine, Tianjin, China.
7. Tianjin Chest Hospital, Tianjin, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Equal contributions of co-corresponding authors. Jihong Han, PhD, College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China. Tel: 86-22-23500522; E-mail: jihonghan2008edu.cn. Yuanli Chen, PhD, Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, China. Tel: 86-18920332280; E-mail: chenyuanliedu.cn. More

Abstract

Rationale: Vascular microcalcification increases the risk of rupture of vulnerable atherosclerotic lesions. Inhibition of ERK1/2 reduces atherosclerosis in animal models while its role in vascular calcification and the underlying mechanisms remains incompletely understood.

Methods: Levels of activated ERK1/2, DKK1, LRP6 and BMP2 in human calcific aortic valves were determined. ApoE deficient mice received ERK1/2 inhibitor (U0126) treatment, followed by determination of atherosclerosis, calcification and miR-126-3p production. C57BL/6J mice were used to determine the effect of U0126 on Vitamin D₃ (VD₃)-induced medial arterial calcification. HUVECs, HAECs and HASMCs were used to determine the effects of ERK1/2 inhibitor or siRNA on SMC calcification and the involved mechanisms.

Results: We observed the calcification in human aortic valves was positively correlated to ERK1/2 activity. At cellular and animal levels, U0126 reduced intimal calcification in atherosclerotic lesions of high-fat diet-fed apoE deficient mice, medial arterial calcification in VD₃-treated C57BL/6J mice, and calcification in cultured SMCs and arterial rings. The reduction of calcification was attributed to ERK1/2 inhibition-reduced expression of ALP, BMP2 and RUNX2 by activating DKK1 and LRP6 expression, and consequently inactivating both canonical and non-canonical Wnt signaling pathways in SMCs. Furthermore, we determined ERK1/2 inhibition activated miR-126-3p production by facilitating its maturation through activation of AMPKα-mediated p53 phosphorylation, and the activated miR-126-3p from ECs and SMCs played a key role in anti-vascular calcification actions of ERK1/2 inhibition.

Conclusions: Our study demonstrates that activation of miR-126-3p production in ECs/SMCs and interactions between ECs and SMCs play an important role in reduction of vascular calcification by ERK1/2 inhibition.

Keywords: ERK1/2, miR-126-3p, vascular calcification, Wnt signaling, ECs

Citation styles

©2024 Ivyspring International Publisher. Terms of use