Key result
GW0742 inhibits neointimal hyperplasia and VSMC proliferation in preclinical models by upregulating FABP3.
Why the study?
In-stent restenosis driven by VSMC phenotypic switching causes poor outcomes, and the role of the PPAR-β/δ agonist GW0742 in neointima formation had not been studied.
Does GW0742 prevent neointima formation and VSMC phenotypic switching in preclinical models of vascular injury?
Does GW0742 prevent neointima formation and VSMC phenotypic switching in preclinical models of vascular injury?
GW0742 prevents neointima formation and preserves the contractile phenotype of vascular smooth muscle cells by upregulating FABP3, highlighting its potential for preventing in-stent restenosis.
May warrant further preclinical testing for restenosis; hypothesis-generating from Level 5 animal data and should not change practice.
Phenotypic switching of vascular smooth muscle cells (VSMCs), leading to neointima formation, is a main cause of in-stent restenosis after coronary stent implantation, resulting in poor patient prognosis. Inhibition of VSMC proliferation, migration, and synthetic phenotype transition holds promise for preventing and treating neointimal hyperplasia and restenosis. GW0742, a peroxisome proliferator-activated receptor (PPAR)-β/δ agonist, has been reported to suppress atherosclerosis and myocardial ischemia-reperfusion injury. However, its role in neointima formation has not been previously studied. In this study, we found that GW0742 significantly inhibited carotid artery injury-induced neointimal hyperplasia in mice. In vitro experiments including cell counting, EdU staining, and proliferation marker detection revealed that GW0742 markedly suppressed Platelet-derived growth factor-BB (PDGF-BB)-induced proliferation of human aortic smooth muscle cells (HASMCs). Flow cytometry analysis showed that GW0742 treatment arrested cells in the G2/M phase. Transwell assays demonstrated that GW0742 inhibited HASMCs migration. Moreover, GW0742 reduced the expression of migration-associated proteins matrix metalloproteinases 2 (MMP2) and matrix metalloproteinases 9 (MMP9), while increasing contractile markers alpha-smooth muscle actin (α-SMA) and calponin 1 (CNN1), suggesting that GW0742 suppresses HASMC proliferation, migration, and phenotypic switching, thereby preserving the contractile phenotype. RNA sequencing revealed that GW0742 regulates fatty acid metabolism by upregulating fatty acid binding protein 3 (FABP3) expression to counteract PDGF-BB-induced VSMC phenotypic switching. Knockdown of FABP3 significantly abrogated the inhibitory effects of GW0742 on VSMC proliferation, migration, and synthetic phenotype transition. Taken together, our findings demonstrate that GW0742 upregulates FABP3 expression, leading to the inhibition of VSMC proliferation, migration, and phenotypic switching, and ultimately suppressing neointima formation. These results underscore the therapeutic potential of GW0742 for the prevention and treatment of vascular restenosis.
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Wang et al. (2026) studied Neointimal hyperplasia and vascular restenosis. GW0742 was evaluated on Neointimal hyperplasia and VSMC proliferation, migration, and phenotypic switching. GW0742 significantly inhibited carotid artery injury-induced neointimal hyperplasia in mice and suppressed proliferation and migration of human aortic smooth muscle cells by upregulating FABP3.
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