PPARγ Agonist Pioglitazone Inhibits PDGF-induced Pulmonary Artery Smooth Muscle Cells Proliferation and Migration via Modulating TERT

Abstract Background: Vascular remodeling is a significant feature of pulmonary artery hypertension (PAH), characterized by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Telomerase reverse transcriptase (TERT) as a determinant factor for controlling telomerase activity has been proved to be associated with cell proliferation. This study aims to explore whether TERT participates in the proliferation of PASMCs and the underlying molecular mechanism. Methods: Primary PASMCs of SD rat were used in this experiment. the proliferation and migration of cells were detected by Cell Counting Kit-8 and transwell assay, respectively. The telomerase activity was determined by Rat TE ELISA KIT. The siRNA transfection was conducted to silence the expression of c-MYC. the protein levels of p-Akt, c-MYC and TERT were determined through western blotting. Results: We found that PDGF upregulated TERT expression and telomerase activation by activation of Akt and upregulation of c-MYC in PASMCs. Inhibition of Akt by LY294002, knockdown of c-MYC by siRNA or suppression of telomerase activity by BIBR1532 repressed PDGF-induced PASMCs proliferation and migration. Furthermore, activation of Peroxisome proliferator-activated receptor γ (PPARγ) by pioglitazone suppressed PDGF-induced TERT expression and telomerase activation, leading to inhibition of PASMCs proliferation and migration.Conclusion: our work demonstrates that TERT mediates PDGF-induced proliferation and migration of PASMCs. In addition, activation of PPARγ inhibits these processes via Akt/c-MYC/TERT pathway.