Activation of PPAR-γ prevents TERT-mediated pulmonary vascular remodeling in MCT-induced pulmonary hypertension.
Activation of PPAR-γ prevents TERT-mediated pulmonary vascular remodeling in MCT-induced pulmonary hypertension.
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DOI：
10.1016/j.heliyon.2023.e14173
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发表时间：
2023-03
期刊：
影响因子：
4
通讯作者：
Xie, Xinming
中科院分区：
文献类型：
--
作者：
Hussain, Tafseel;Chai, Limin;Wang, Yan;Zhang, Qianqian;Wang, Jian;Shi, Wenhua;Wang, Qingting;Li, Manxiang;Xie, Xinming
关键词：
研究表明，肺动脉高压（PH）与端粒酶逆转录酶（TERT）表达或活性升高有关。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的发病机制中负责PPAR-γ活化对TERT表达的保护作用的分子机制仍然未知。本研究旨在解决这些问题。腹腔注射野百合碱（MCT）建立PH，应用BIBR 1532抑制端粒酶活性。采用右心室收缩压（RVSP）和组织学方法检测PH的发生发展，采用Western blotting检测p-Akt、t-Akt、c-Myc和TERT蛋白水平。BIBF 1532对TERT的药理学抑制作用有效抑制了MCT诱导的PH大鼠的RVSP、RVHI和WT%。LY 294002对Akt/c-Myc通路的药理学抑制可降低MCT-PH大鼠中的TERT上调、RVSP、RVHI和WT%。吡格列酮激活PPAR-γ可抑制p-Akt和c-Myc表达，并进一步下调TERT，从而降低MCT处理PH大鼠的RVSP、RVHI和WT%。总之，TERT上调有助于MCT给药大鼠的PH发展。激活PPAR-γ通过抑制Akt/c-Myc/TERT轴阻止肺动脉重构。
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.
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DOI：
10.1152/ajplung.00245.2017
发表时间：
2018-03-01
影响因子：
4.9
作者：
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