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Updated: Aug 5, 2026
A Rat Carotid Artery Pressure-Controlled Segmental Balloon Injury with Periadventitial Therapeutic Application
Published on: July 9, 2020
TRIM24 Impediment suppresses VSMC modulation and attenuates neointimal hyperplasia via redox and autophagy pathways
Monika Singh1, Ankan Sarkar1, Zahid Bashir Zargar1
1Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, 160014, Chandigarh, India.
Background:
Excessive vascular smooth muscle cell (VSMC) proliferation/survival is a critical event underlying restenosis and vascular remodeling. Tripartite motif-containing 24 (TRIM24) is an oncogenic TRIM family protein with E3 ubiquitin ligase and transcriptional co-regulator functions. This study aimed to elucidate the critical role of TRIM24 in modulating VSMC functions and neointimal hyperplasia.
Methods And Results:
Our in-silico network pharmacology analysis revealed that the TRIM24 inhibitor, IACS-9571, engages multiple hub genes and key pathways involved in VSMC proliferation, apoptosis, autophagy, migration, and extracellular matrix remodeling. Using Western blot and immunofluorescence analysis, we found that platelet-derived growth factor-BB (PDGF-BB) stimulation of murine primary aortic VSMCs, significantly upregulated TRIM24 expression. SiRNA-mediated knockdown of TRIM24 attenuated PDGF-BB-induced VSMC proliferation. Pharmacological inhibition of TRIM24 using IACS-9571 markedly suppressed PDGF-BB-induced VSMC proliferation, migration, and phenotypic switching. Furthermore, TRIM24 blockade enhanced autophagy in VSMCs, as evidenced by elevated LC3 and Beclin-1 protein levels, accumulation of LC3 puncta and transcriptional upregulation of autophagy-related genes, namely ATG7 and ATG4B. Also, TRIM24 inhibition reduced AKT and mTOR activation compared to PDGF-BB-stimulated VSMCs. Concurrently, TRIM24 inhibition elevated mitochondrial ROS levels, upregulated BAX expression, a pro-apoptotic gene, and significantly enhanced apoptosis, as confirmed by TUNEL and Annexin V/PI assays. In vivo, Immunofluorescence analysis demonstrated elevated TRIM24 expression within the neointimal regions. Perivascular application of the TRIM24 inhibitor prevented wire injury-induced neointimal hyperplasia.
Conclusion:
These findings identify TRIM24 as a key regulator of VSMC proliferation, migration, and phenotypic switching. Targeting TRIM24 promotes autophagy and induces apoptosis, offering a promising strategy to limit neointimal hyperplasia and pathological vascular remodeling.
