Inhibition of PIKfyve Ameliorates the Proliferation and Migration of Vascular Smooth Muscle Cells and Vascular Intima Hyperplasia By Reducing mTORC1 Activity.

Abstract

ABSTRACT:

This study was designed to investigate the role and mechanism of PIKfyve in the proliferation and migration of vascular smooth muscle cells (VSMCs) and vascular intima hyperplasia. We first observed increased protein levels of PIKfyve, phospho (p)-S6 Ribosomal Protein (S6)Ser235/236, p-4EBP1Thr37/46 in VSMCs after 24 hours of platelet-derived growth factor (PDGF)-BB treatment. By using cell counting kit-8 assay, Ki-67 immunofluorescence staining and wound healing assay, we found that PIKfyve inhibition ameliorated the enhanced activity of VSMC proliferation and migration induced by PDGF-BB. Silencing PIKfyve also suppressed the phosphorylation of S6 and 4EBP1 (2 major effectors of mammalian target of rapamycin complex 1), glucose consumption, activity of hexokinase, and LDH in PDGF-BB-challenged VSMCs. After rescuing the phosphorylation of S6 and 4EBP1 by silencing Tsc1, the suppressive effects of PIKfyve inhibition on glucose utilization, proliferation, and migration in VSMCs were abolished. The animal model of vascular restenosis was established in C57BL/6J mice by wire injury. We found the expression of PIKfyve was increased in carotid artery at day 28 after injury. Reducing the activity of PIKfyve alleviated vascular neointima hyperplasia after injury. In conclusion, targeting PIKfyve might be a novel effective method to reduce the proliferation and migration of VSMCs and vascular restenosis by affecting mammalian target of rapamycin complex 1-mediated glucose utilization.

• Authors: Min Gu, Zhen Wang, Feifei Feng, Yongjian Yang, Xiongshan Sun, Dachun Yang
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 79 Issue 5 Pg. 739-748 (05 01 2022) ISSN: 1533-4023 [Electronic] United States
• PMID: 35275098 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Chemical References

• Becaplermin
• Pikfyve protein, mouse
• Mechanistic Target of Rapamycin Complex 1
• Glucose

Topics

• Animals
• Becaplermin (pharmacology)
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Glucose (metabolism)
• Hyperplasia (metabolism, pathology)
• Mammals
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Mice
• Mice, Inbred C57BL
• Muscle, Smooth, Vascular (metabolism)
• Myocytes, Smooth Muscle (metabolism)
• Neointima (metabolism, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Tunica Intima