Hussain Tafseel, Chai Limin, Wang Yan, Zhang Qianqian, Wang Jian, Shi Wenhua, Wang Qingting, Li Manxiang, Xie Xinming
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
Heliyon. 2023 Mar 4;9(3):e14173. doi: 10.1016/j.heliyon.2023.e14173. eCollection 2023 Mar.
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.
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.
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.
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.
已证实端粒酶逆转录酶（TERT）表达或活性升高与肺动脉高压（PH）有关。此外，已发现过氧化物酶体增殖物激活受体γ（PPAR-γ）的激活可预防PH进展。然而，在PH发病机制中，PPAR-γ激活对TERT表达的保护作用的分子机制仍不清楚。本研究旨在解决这些问题。
腹腔注射野百合碱（MCT）建立PH模型。应用BIBR1532抑制端粒酶活性。采用右心室收缩压（RVSP）和组织学分析检测PH的发展。通过蛋白质印迹法测定p-Akt、t-Akt、c-Myc和TERT的蛋白水平。BIBR1532对TERT的药理学抑制有效抑制了MCT诱导的PH大鼠的RVSP、RVHI和WT%。
LY294002对Akt/c-Myc途径的药理学抑制减少了MCT-PH大鼠中TERT的上调、RVSP、RVHI和WT%。吡格列酮激活PPAR-γ抑制了p-Akt和c-Myc的表达，并进一步下调了TERT，从而降低了MCT治疗的PH大鼠的RVSP、RVHI和WT%。
总之，TERT上调促进了MCT处理大鼠的PH发展。PPAR-γ的激活通过抑制Akt/c-Myc/TERT轴来防止肺动脉重塑。
