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Total Panax notoginseng saponin inhibits vascular smooth muscle cell proliferation and migration and intimal hyperplasia by regulating WTAP/p16 signals via m6A modulation.

Abstract
Intimal hyperplasia, the key event of arterial restenosis, is a result of vascular smooth muscle cell (VSMC) proliferation and migration. Previous studies have demonstrated that total Panax notoginseng saponin (TPNS) represses intimal hyperplasia and inhibits the proliferation of VSMCs following balloon injury. However, the underlying roles of TPNS in intimal hyperplasia remain unclear. In this study, we first found that TPNS inhibited the intimal hyperplasia and reversed the reduced m6A quantity in balloon catheter-injured rat carotid artery. Then, we measured the expression profiles of m6A "writers" (i.e., methyltransferase like 3 (METTL3), methyltransferase like 14 (METTL14), and WT1 associated protein (WTAP)) and "erasers" (i.e., FTO alpha-ketoglutarate dependent dioxygenase (FTO) and alkB homolog 5, RNA demethylase (ALKBH5)) in vivo and found that TPNS up-regulated the reduced the WTAP expression in balloon catheter-injured rat carotid artery. Furthermore, we illustrated that TPNS inhibited the viability, proliferation, and migration potential of VSMCs via promotion of WTAP expression and suppression of WTAP restored the TPNS-induced inhibition of cell viability, proliferation and migration potential of VSMCs. In addition, we found that p16 was up-regulated in VSMCs treated with TPNS and repression of p16 restored the TPNS-induced inhibition of cell viability, proliferation and migration potential of VSMCs. Finally, we elucidated that, mechanistically, WTAP exerted its role by regulating p16 via m6A modification. Collectively, our results reveal the WTAP-p16 signaling axis and highlight the critical roles of m6A modification in intimal hyperplasia. Thus, this study provided a potential biomarker for the assessment of intimal hyperplasia risk following angioplasty as well as a novel therapeutic target for this disease.
AuthorsBoqian Zhu, Yaoyao Gong, Le Shen, Jie Li, Jie Han, Bingzhan Song, Lianxia Hu, Qingjie Wang, Zhenxing Wang
JournalBiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 124 Pg. 109935 (Apr 2020) ISSN: 1950-6007 [Electronic] France
PMID31986407 (Publication Type: Journal Article)
CopyrightCopyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
Chemical References
  • Cyclin-Dependent Kinase Inhibitor p16
  • Saponins
  • WT1 Proteins
  • N-methyladenosine
  • Adenosine
Topics
  • Adenosine (analogs & derivatives, metabolism)
  • Animals
  • Carotid Artery Injuries (drug therapy, pathology)
  • Cell Movement (drug effects)
  • Cell Proliferation (drug effects)
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
  • Humans
  • Hyperplasia (drug therapy)
  • Male
  • Muscle, Smooth, Vascular (cytology, drug effects)
  • Panax notoginseng (chemistry)
  • Rats
  • Rats, Sprague-Dawley
  • Saponins (isolation & purification, pharmacology)
  • Signal Transduction (drug effects)
  • Tunica Intima (drug effects, pathology)
  • WT1 Proteins (metabolism)

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