Metformin Inhibits Angiogenesis of Endothelial Progenitor Cells via miR-221-mediated p27 Expression and Autophagy

Abstract

Aim: To explore the underlying mechanisms of metformin on the angiogenic capacity of endothelial progenitor cells (EPCs). Results: EPC growth and miR-221 expression decreased concentration-dependence with metformin, and a negative correlation was observed between miR-221 expression and metformin concentration (p < 0.001). miR-221 overexpression using a mimic decreased the metformin-mediated angiogenic effects in EPCs (p < 0.01). Metformin increased p27 and LC3II expression and AMP-activated protein kinase (AMPK) phosphorylation, and decreased p62 expression, while miR-221 overexpression reversed the effects of metformin. Additionally, AMPK inhibition by compound C reversed the increase in p27 and LC3II levels and AMPK phosphorylation or miR-221 siRNA treatment. Conclusion: Metformin inhibits the angiogenic capacity of EPCs. The underlying mechanism involves AMPK-mediated autophagy pathway activity and increases miR-221-mediated p27 expression.

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Keywords: :

• angiogenesis
• autophagy
• endothelial progenitor cells
• metformin
• miR-221
• p27

Financial & competing interests disclosure

This work was supported by grants from the National Natural Science Foundation of China (no. 81770483, 81800418), the Natural Science Foundation of Jiangsu Province (no. BK20180125), the Key Project supported by Medical Science and technology development Foundation (no. YKK18063), Nanjing Department of Health, the Fundamental Research Funds for the Central Universities (no. 021414380362). We thank R Robins, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.