Lithium Chloride Inhibits Vascular Smooth Muscle Cell Proliferation and Migration and Alleviates Injury-Induced Neointimal Hyperplasia via Induction of PGC-1α

Zhuyao Wang,Jun Wu,Danfeng Wang,Chang Liu,Siyu Chen,Tingming Liang,Xiwen Zhang,Qingzhong Xiao

doi:10.1371/journal.pone.0055471

Abstract

The proliferation and migration of vascular smooth muscle cells (VSMCs) contributes importantly to the development of in-stent restenosis. Lithium has recently been shown to have beneficial effects on the cardiovascular system, but its actions in VSMCs and the direct molecular target responsible for its action remains unknown. On the other hand, PGC-1α is a transcriptional coactivator which negatively regulates the pathological activation of VSMCs. Therefore, the purpose of the present study is to determine if lithium chloride (LiCl) retards VSMC proliferation and migration and if PGC-1α mediates the effects of lithium on VSMCs. We found that pretreatment of LiCl increased PGC-1α protein expression and nuclear translocation in a dose-dependent manner. MTT and EdU incorporation assays indicated that LiCl inhibited serum-induced VSMC proliferation. Similarly, deceleration of VSMC migration was confirmed by wound healing and transwell assays. LiCl also suppressed ROS generation and cell cycle progression. At the molecular level, LiCl reduced the protein expression levels or phosphorylation of key regulators involved in the cell cycle re-entry, adhesion, inflammation and motility. In addition, in vivo administration of LiCl alleviated the pathophysiological changes in balloon injury-induced neointima hyperplasia. More importantly, knockdown of PGC-1α by siRNA significantly attenuated the beneficial effects of LiCl on VSMCs both in vitro and in vivo. Taken together, our results suggest that LiCl has great potentials in the prevention and treatment of cardiovascular diseases related to VSMC abnormal proliferation and migration. In addition, PGC-1α may serve as a promising drug target to regulate cardiovascular physiological homeostasis.

Highlights

The proliferation and migration of vascular smooth muscle cells (VSMCs) is the major underlying biological process of pathological conditions such as in-stent restenosis
Pharmaceutical companies have spent great efforts in developing novel discovery technologies, such as structure-based drug design, combinatorial chemistry, high-throughput screening and genomics, the output is far less than the enormous increases in pharma R&D spending and this has become a severe problem for the biopharmaceutical industry [19]
Based on the previous reports, we found that lithium chloride (LiCl) increases PGC-1a protein expression and nuclear translocation in VSMCs (Fig. 1), while inhibits serum-induced cell proliferation and migration (Fig. 2), ROS generation (Fig. 3) and cell cycle re-entry (Fig. 4)

Summary

Introduction

The proliferation and migration of vascular smooth muscle cells (VSMCs) is the major underlying biological process of pathological conditions such as in-stent restenosis. When the endothelial injury is induced by balloon catheterization or stent placement, it will stimulate VSMCs to migrate from the medial and the adventitial layers to the intimal layer of the vessel wall where they proliferate [1]. The formation of this neointima is an important architectural change in the vessel wall that leads to restenosis after angioplasty or stenting [2]. A strategy aiming to inhibit VSMC growth and migration has high value in the prevention and attenuation of in-stent restenosis upon percutaneous transluminal coronary angioplasty (PTCA)

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