PPARγ attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells

Aims Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been reported to attenuate intimal hyperplasia. This study aimed to test the hypothesis that PPAR gamma inhibits intimal hyperplasia through suppressing Toll-like receptor 4 (TLR4)-mediated inflammation in vascular smooth muscle cells. Methods and results TLR4(-/-) mice on a C57BL/6J background were used. Increased TLR4 and pro-inflammatory cytokines were observed in wire-injury-induced carotid neointima and in platelet-derived growth factor (PDGF)-activated vascular smooth muscle cells. The TLR4 deficiency protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to lipopolysaccharide and PDGF. Rosiglitazone attenuated intimal hyperplasia. Overexpression of PPAR gamma suppressed PDGF-induced proliferation and migration and inhibited TLR4-mediated inflammation in vascular smooth muscle cells, while PPAR gamma silencing exerted the opposite effect. Lipopolysaccharide counteracted the inhibitory effect of PPAR gamma on PDGF-induced proliferation and migration. Eritoran suppressed the proliferation and migration induced by PDGF and PPAR gamma silencing. Vascular smooth muscle cells derived from TLR4(-/-) mice showed impaired proliferation and migration upon PDGF activation and displayed no response to PPAR gamma manipulation. Conclusion PPAR gamma inhibits vascular smooth muscle cell proliferation and migration by suppressing TLR4-mediated inflammation and ultimately attenuates intimal hyperplasia after carotid injury.