Differential expression of PPARγ by pioglitazone and telmisartan causes effect of disparity on mTORC2-mediated cell proliferation and migration.

Excessive cell proliferation and migration of vascular smooth muscle cells (VSMCs) exacerbate atherosclerotic plaque formation. Peroxisome proliferation-activated receptor gamma (PPARγ) has an atheroprotective effect by inhibiting foam cell formation in macrophages. However, the anti-proliferative mechanism of PPARγ has not been fully explained in VSMCs. Therefore, we investigated the effect of PPARγ by full or partial agonist on VSMC proliferation and migration to suppress atherosclerosis. We found that PPARγ activation by pioglitazone (a full agonist) decreased PDGF-BB-induced mTORC2 signaling pathway and cell proliferation. Pioglitazone treatment downregulated the expression of VSMC contractile markers, cell migration, and lipid accumulation. In contrast, a PPARγ partial agonist, telmisartan, did not influence mTORC2 signaling pathway, VSMC phenotype switching, and lipid droplet markers despite PPARγ activation. We identified differential expression of PPARγ between pioglitazone and telmisartan to regulate VSMC phenotype switching and atherosclerosis. The anti-proliferative effect of pioglitazone was attributed to inhibition of mTORC2 activation, leading to atheroprotective effect. Our findings show that PPARγ suppresses mTORC2 signaling pathway to mitigate VSMC proliferation and migration, which accelerates the atherosclerosis development. These results demonstrate that full and partial PPARγ agonists exert different effects through specific mechanisms, respectively, despite both agonists against PPARγ.