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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism
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Cell Cycle / drug effects
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Cell Movement / drug effects*
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Cell Nucleus / metabolism
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Cell Proliferation / drug effects
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Cells, Cultured
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Gene Expression Regulation / drug effects
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Hyperplasia
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Lithium Chloride / pharmacology*
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Male
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects*
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Myocytes, Smooth Muscle / drug effects*
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Myocytes, Smooth Muscle / metabolism
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Neointima / metabolism*
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Neointima / pathology*
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Protein Transport
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Rats
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Vascular Endothelial Growth Factors / metabolism
Substances
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Cell Adhesion Molecules
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, rat
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RNA-Binding Proteins
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Reactive Oxygen Species
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Transcription Factors
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Vascular Endothelial Growth Factors
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Lithium Chloride
Grants and funding
This work was supported by grants from the National Basic Research Program of China (973 Program) (2012CB947600), the Program for New Century Excellent Talents in University by the Chinese Ministry of Education (NCET), the National Natural Science Foundation of China (31171137, 31271261), the Key Project of Chinese Ministry of Education (211062), the Research Fund for the Doctoral Program of Higher Education of China (20103207110007), the Fok Ying Tong Education Foundation (121022), the Major Program of Educational Commission of Jiangsu Province (09KJA180004) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.