Academic Journal
Elafibranor inhibits neointima formation by downregulating CDK1 expression in carotid artery injury mice model.
| Τίτλος: | Elafibranor inhibits neointima formation by downregulating CDK1 expression in carotid artery injury mice model. |
|---|---|
| Συγγραφείς: | Wang X; Department of Cardiology, Tongren People's Hospital, Tongren, Guizhou, China., Chen J; Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China., Huo B; Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China., Lin W; Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China., Jiang DS; Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, NHC Key Laboratory of Organ Transplantation, Wuhan, Hubei, China., Cheng W; Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, Hubei, China., Zhao F; Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, Hubei, China. Electronic address: cedilanid@163.com., Gong FH; Department of Cardiology, Tongren People's Hospital, Tongren, Guizhou, China. Electronic address: gongfh@whu.edu.cn. |
| Πηγή: | European journal of pharmacology [Eur J Pharmacol] 2026 Jun 28; Vol. 1028, pp. 178950. Date of Electronic Publication: 2026 May 17. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2005- : Amsterdam : Elsevier Science Original Publication: Amsterdam, North Holland Pub. Co. |
| Ιατρικοί όροι (MeSH): | Neointima*/pathology , Neointima*/drug therapy , Carotid Artery Injuries*/pathology , Carotid Artery Injuries*/drug therapy , Carotid Artery Injuries*/metabolism , Down-Regulation*/drug effects , CDC2 Protein Kinase*/genetics , CDC2 Protein Kinase*/metabolism, Cell Proliferation/drug effects ; Cell Movement/drug effects ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/pathology ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/pathology ; Matrix Metalloproteinase 9/metabolism ; Matrix Metalloproteinase 2/metabolism ; Animals ; Mice ; Male ; Disease Models, Animal ; Mice, Inbred C57BL |
| Περίληψη: | 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. (Copyright © 2026 Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: CDK1/CDC2; Elafibranor; Neointima formation; Restenosis |
| Substance Nomenclature: | EC 2.7.11.22 (CDC2 Protein Kinase) EC 2.7.11.22 (Cdk1 protein, mouse) EC 3.4.24.35 (Matrix Metalloproteinase 9) EC 3.4.24.24 (Matrix Metalloproteinase 2) |
| Entry Date(s): | Date Created: 20260518 Date Completed: 20260613 Latest Revision: 20260613 |
| Update Code: | 20260615 |
| DOI: | 10.1016/j.ejphar.2026.178950 |
| PMID: | 42150712 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1879-0712 |
|---|---|
| DOI: | 10.1016/j.ejphar.2026.178950 |