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Differential expression of PPARγ by pioglitazone and telmisartan causes effect of disparity on mTORC2-mediated cell
Seul Gi Kim1,2, Jin Young Sung1,2, So-Young Park3,2
1Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu, 42415, Republic of Korea.
Abstract:
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.
Insights
Full PPARγ agonists like pioglitazone inhibit mTORC2 signaling, reducing vascular smooth muscle cell proliferation and migration to protect against atherosclerosis. Partial agonists show different effects.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pharmacology
Background:
- Vascular smooth muscle cell (VSMC) proliferation and migration contribute to atherosclerotic plaque formation.
- Peroxisome proliferation-activated receptor gamma (PPARγ) exhibits atheroprotective effects, but its anti-proliferative mechanism in VSMCs requires further elucidation.
Purpose of the Study:
- To investigate the distinct effects of full and partial PPARγ agonists on VSMC proliferation and migration in the context of atherosclerosis suppression.
Main Methods:
- Activation of PPARγ using pioglitazone (full agonist) and telmisartan (partial agonist).
- Assessment of mTORC2 signaling pathway activity.
- Evaluation of VSMC contractile markers, cell migration, and lipid accumulation.
- Analysis of differential PPARγ expression patterns.
Main Results:
- Pioglitazone significantly decreased PDGF-BB-induced mTORC2 signaling, VSMC proliferation, contractile marker expression, migration, and lipid accumulation.
- Telmisartan, despite activating PPARγ, did not affect mTORC2 signaling, VSMC phenotype switching, or lipid droplet markers.
- Differential PPARγ expression was identified between pioglitazone and telmisartan treatments, influencing VSMC phenotype and atherosclerosis.
Conclusions:
- PPARγ activation by full agonists, such as pioglitazone, suppresses VSMC proliferation and migration via inhibition of mTORC2 signaling, conferring an atheroprotective effect.
- Full and partial PPARγ agonists exert distinct mechanistic effects on VSMC phenotype switching and atherosclerosis progression.
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