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Updated: May 20, 2026
Vascular Balloon Injury and Intraluminal Administration in Rat Carotid Artery
Published on: December 23, 2014
Elafibranor inhibits neointima formation by downregulating CDK1 expression in carotid artery injury mice model
Xuesheng Wang1, Jingjie Chen2, Bo Huo2
1Department of Cardiology, Tongren People's Hospital, Tongren, Guizhou, China.
Abstract:
In-stent restenosis remains a major challenge in coronary artery disease management. The proliferation, migration, and phenotypic switching of vascular smooth muscle cells (VSMCs) are key drivers of neointimal hyperplasia and restenosis. Pharmacological agents targeting these processes may therefore offer a strategy to prevent or treat neointima formation. Here, we demonstrate that elafibranor (also known as GFT505), a dual agonist of peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator-activated receptor delta (PPARδ), significantly reduced neointima formation in a mouse model of carotid artery injury. In vitro, PDGF-BB stimulation induced VSMC proliferation, migration, and a phenotypic switch towards a synthetic state-all of which were markedly suppressed by elafibranor. Cell Counting Kit-8 assays, 5-Ethynyl-2'-deoxyuridine (EdU) incorporation, and proliferation markers (phosphorylated histone H3 (Ser10) and Proliferating Cell Nuclear Antigen (PCNA)) indicated that elafibranor inhibited VSMC proliferation primarily by inducing cell cycle arrest at the G2/M phase. Transwell assays and reduced expression of matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9) pointed to a significant inhibition of VSMC migration. In addition, elafibranor suppressed the transition of VSMCs from a contractile to a synthetic phenotype, as shown by changes in marker expression. Mechanistically, transcriptome sequencing with Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) analyses revealed that elafibranor modulated pathways linked to cell proliferation and cycle control. In particular, it downregulated cyclin-dependent kinase 1 (CDK1), a key regulator of the G2/M checkpoint. Overexpression of CDK1 reversed the inhibitory effects of elafibranor on VSMC proliferation, migration, and phenotypic switching. Together, these findings identify elafibranor as a potential therapeutic agent capable of suppressing neointimal hyperplasia, pointing to a new approach for preventing and treating in-stent restenosis.
Insights
Elafibranor, a dual PPARα/δ agonist, effectively reduces neointimal hyperplasia by inhibiting vascular smooth muscle cell proliferation and migration. This offers a promising therapeutic strategy for preventing in-stent restenosis after coronary artery injury.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Cell Biology
Background:
- In-stent restenosis is a significant complication of coronary artery disease.
- Vascular smooth muscle cell (VSMC) proliferation, migration, and phenotypic switching drive neointimal hyperplasia.
- Targeting these VSMC processes presents a therapeutic opportunity.
Purpose of the Study:
- To investigate the efficacy of elafibranor, a dual peroxisome proliferator-activated receptor alpha (PPARα) and PPARδ agonist, in preventing neointimal hyperplasia.
- To elucidate the mechanisms by which elafibranor affects VSMC behavior.
Main Methods:
- A mouse model of carotid artery injury was used to assess neointima formation in vivo.
- In vitro studies utilized PDGF-BB stimulated VSMCs to evaluate proliferation, migration, and phenotypic switching.
- Cell cycle analysis, gene expression profiling (RNA-seq), and pathway analysis (KEGG, GO, GSEA) were employed.
Main Results:
- Elafibranor significantly reduced neointima formation in vivo.
- In vitro, elafibranor inhibited VSMC proliferation via G2/M cell cycle arrest, suppressed migration by downregulating MMP2/MMP9, and prevented phenotypic switching.
- Transcriptome analysis revealed elafibranor's modulation of cell proliferation and cycle control pathways, including downregulation of cyclin-dependent kinase 1 (CDK1).
Conclusions:
- Elafibranor demonstrates potent anti-proliferative and anti-migratory effects on VSMCs.
- The drug acts by inducing cell cycle arrest and modulating key signaling pathways, notably CDK1.
- Elafibranor represents a potential therapeutic agent for managing in-stent restenosis by suppressing neointimal hyperplasia.
