Activation of PPAR-γ prevents TERT-mediated pulmonary vascular remodeling in MCT-induced pulmonary hypertension

Tafseel Hussain; Limin Chai; Yan Wang; Qianqian Zhang; Jian Wang; Wenhua Shi; Qingting Wang; Manxiang Li; Xinming Xie

doi:10.1016/j.heliyon.2023.e14173

Activation of PPAR-γ prevents TERT-mediated pulmonary vascular remodeling in MCT-induced pulmonary hypertension

Heliyon. 2023 Mar 4;9(3):e14173. doi: 10.1016/j.heliyon.2023.e14173. eCollection 2023 Mar.

Authors

Tafseel Hussain¹, Limin Chai¹, Yan Wang¹, Qianqian Zhang¹, Jian Wang¹, Wenhua Shi², Qingting Wang¹, Manxiang Li¹, Xinming Xie¹

Affiliations

¹ Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
² Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.

Abstract

Background: It has been demonstrated that elevated telomerase reverse transcriptase (TERT) expression or activity is implicated in pulmonary hypertension (PH). In addition, activation of peroxisome-proliferator-activated receptor γ (PPAR-γ) has been found to prevent PH progression. However, the molecular mechanism responsible for the protective effect of PPAR-γ activation on TERT expression in the pathogenesis of PH remains unknown. This study was performed to address these issues.

Methods: Intraperitoneal injection of monocrotaline (MCT) was used to establish PH. BIBR1532 was applied to inhibit the activity of telomerase. The right ventricular systolic pressure (RVSP) and histological analysis were used to detect the development of PH. The protein levels of p-Akt, t-Akt, c-Myc and TERT were determined by western blotting. Pharmacological inhibition of TERT by BIBR1532 effectively suppressed RVSP, RVHI and the WT% in MCT-induced PH rats.

Results: Pharmacological inhibition of Akt/c-Myc pathway by LY294002 diminished TERT upregulation, RVSP, RVHI and WT% in MCT-PH rats. Activation of PPAR-γ by pioglitazone inhibited p-Akt and c-Myc expressions and further downregulated TERT, thus to reduced RVSP, RVHI and WT% in MCT-treated PH rats.

Conclusions: In conclusion, TERT upregulation contributes to PH development in MCT-treated rats. Activation of PPAR-γ prevents pulmonary arterial remodeling through Akt/c-Myc/TERT axis suppression.

Keywords: Akt/c-Myc; Peroxisome proliferator-activated receptor γ; Pulmonary artery hypertension; Pulmonary vascular remodeling; Telomerase; Telomerase reverse transcriptase.