Tribbles Homolog 3-Mediated Vascular Insulin Resistance Contributes to Hypoxic Pulmonary Hypertension in Intermittent Hypoxia Rat Model.
Tribbles Homolog 3-Mediated Vascular Insulin Resistance Contributes to Hypoxic Pulmonary Hypertension in Intermittent Hypoxia Rat Model.
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Tribbles 同源物 3 介导的血管胰岛素抵抗导致间歇性缺氧大鼠模型中的缺氧性肺动脉高压
DOI：
10.3389/fphys.2020.542146
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发表时间：
2020
影响因子：
4
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Fan F;He J;Su H;Zhang H;Wang H;Dong Q;Zeng M;Xing W;Sun X
本研究旨在探讨血管胰岛素抵抗(VIR)和Tribble同系物3(TRIB3)在缺氧性肺动脉高压(HPH)发病中的作用。采用低气压、低氧间歇暴露4周建立大鼠HPH模型。HPH大鼠的平均右室压(MRVP)、平均肺动脉压(MPAP)和右室指数(RVI)均显著升高。HPH大鼠的肺动脉呈VIR，胰岛素的血管扩张作用减弱。PPARγ、PI3K、AKT磷酸化和内皮型一氧化氮合酶(ENOS)蛋白水平降低，TRIB3和磷酸化细胞外信号调节蛋白激酶(ERK1/2)升高。早期应用吡格列酮(PIO)可部分逆转HPH的发展，改善胰岛素诱导的血管扩张，减轻胰岛素信号的失衡。大鼠肺动脉内皮细胞过表达TRIB3后，PPARγ、PI3K、磷酸化Akt(p-Akt)和磷酸化eNOS(p-eNOS)水平降低，p-ERK1/2和内皮素-1(ET-1)合成增加，这种作用在缺氧条件下进一步增强。此外，TRIB3基因敲除可显著改善缺氧后血管内皮细胞Akt和eNOS的磷酸化，降低ERK1/2的活性。综上所述，胰岛素诱导的肺血管扩张功能受损和内皮细胞TRIB3上调介导的胰岛素诱导的信号传导失衡参与了HPH的发生发展。早期PIO治疗可改善血管胰岛素敏感性，这可能有助于限制缺氧性肺动脉高压的进展。
This study aimed to investigate the role of vascular insulin resistance (VIR) and Tribbles homolog 3 (TRIB3) in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH). Rats were subjected to low air pressure and low oxygen intermittently for 4 weeks to induce HPH. The mean right ventricular pressure (mRVP), mean pulmonary arterial pressure (mPAP), and right ventricular index (RVI) were significantly increased in HPH rats. Pulmonary arteries from HPH rats showed VIR with reduced vasodilating effect of insulin. The protein levels of peroxisome proliferator-activated receptor gamma (PPARγ), phosphoinositide 3-kinase (PI3K), phosphorylations of Akt, and endothelial nitric oxide (NO) synthase (eNOS) were decreased, and TRIB3 and phosphorylated extracellular signal-regulated protein kinases (ERK1/2) were increased in pulmonary arteries of HPH rats. Early treatment of pioglitazone (PIO) partially reversed the development of HPH, improved insulin-induced vasodilation, and alleviated the imbalance of the insulin signaling. The overexpression of TRIB3 in rat pulmonary arterial endothelial cells (PAECs) reduced the levels of PPARγ, PI3K, phosphorylated Akt (p-Akt), and phosphorylated eNOS (p-eNOS) and increased p-ERK1/2 and the synthesis of endothelin-1 (ET-1), which were further intensified under hypoxic conditions. Moreover, TRIB3 knockdown caused significant improvement in Akt and eNOS phosphorylations and, otherwise, a reduction of ERK1/2 activation in PAECs after hypoxia. In conclusion, impaired insulin-induced pulmonary vasodilation and the imbalance of insulin-induced signaling mediated by TRIB3 upregulation in the endothelium contribute to the development of HPH. Early PIO treatment improves vascular insulin sensitivity that may help to limit the progression of hypoxic pulmonary hypertension.
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DOI：
10.1073/pnas.1214014110
发表时间：
2013-01-29
影响因子：
11.1
作者：
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影响因子：
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DOI：
10.1152/ajpendo.00663.2011
发表时间：
2012-10-01
影响因子：
5.1
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影响因子：
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