GW0742 prevents neointima formation by upregulating FABP3 expression

Area of Science:

• Cardiovascular Biology
• Pharmacology
• Cell Biology

Background:

• Vascular smooth muscle cell (VSMC) phenotypic switching drives neointima formation, a key factor in in-stent restenosis.
• Inhibiting VSMC proliferation, migration, and synthetic phenotype is crucial for preventing restenosis.
• GW0742, a PPAR-β/δ agonist, has shown promise in other cardiovascular conditions but its role in neointima formation was unknown.

Purpose of the Study:

• To investigate the effect of GW0742 on neointima formation.
• To elucidate the underlying mechanisms of GW0742's action on VSMCs.
• To assess GW0742's therapeutic potential for vascular restenosis.

Main Methods:

• In vivo carotid artery injury model in mice.
• In vitro studies using human aortic smooth muscle cells (HASMCs) treated with PDGF-BB.
• Cell counting, EdU staining, flow cytometry, Transwell assays, Western blotting, and RNA sequencing.
• FABP3 knockdown experiments.

Main Results:

• GW0742 significantly inhibited neointimal hyperplasia in vivo.
• GW0742 suppressed PDGF-BB-induced HASMC proliferation and migration in vitro.
• GW0742 induced G2/M cell cycle arrest and modulated VSMC phenotype markers (α-SMA, CNN1, MMP2, MMP9).
• GW0742 upregulated FABP3 expression, which was essential for its inhibitory effects.

Conclusions:

• GW0742 effectively inhibits VSMC proliferation, migration, and phenotypic switching.
• Upregulation of FABP3 by GW0742 is a key mechanism in suppressing neointima formation.
• GW0742 demonstrates significant therapeutic potential for preventing and treating vascular restenosis.