Mutual promotion of FGF21 and PPARγ attenuates hypoxia-induced pulmonary hypertension
Mutual promotion of FGF21 and PPARγ attenuates hypoxia-induced pulmonary hypertension
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FGF21 和 PPAR γ 的相互促进可减轻缺氧引起的肺动脉高压
DOI：
10.1177/1535370219828692
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发表时间：
2019-03-01
影响因子：
3.2
通讯作者：
Huang, Xiaoying
中科院分区：
文献类型：
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作者：
Cai, Gexiang;Liu, Jingjing;Huang, Xiaoying
成纤维细胞生长因子21（FGF 21）是一种主要来源于肝脏的内分泌因子，具有保护血管的有益作用。过氧化物酶体增殖物激活受体γ（Peroxisome proliferator-activated receptor gamma，PPAR gamma）是一种配体激活的核转录因子，能有效抑制肺动脉高压（pulmonary hypertension，PH）。本研究旨在探讨FGF 21在缺氧诱导的肺高压（HPH）中的作用及其与过氧化物酶体增殖物激活受体γ（PPAR γ）的关系。成年C57 BL/6小鼠经4周缺氧建立PH模型。在HPH小鼠中研究了FGF 21和PPAR γ激动剂和拮抗剂的作用，以及在该模型中FGF 21和PPAR γ之间的关系。此外，我们研究了体内和体外FGF 21和PPAR γ之间这种关系的潜在机制。在体内，我们发现缺氧导致肺动脉高压、右心室肥大、肺动脉重构和肺动脉胶原沉积。此外，缺氧降低FGF 21和PPAR γ水平。这些变化被外源性FGF 21和PPAR γ激动剂逆转，并被PPAR γ拮抗剂进一步增强。低氧诱导的β-klotho（KLB）表达减少通过PPAR γ激动剂改善，并通过PPAR γ拮抗剂进一步降低。外源性FGF 21增加PH小鼠肺匀浆中腺苷一磷酸活化蛋白激酶（AMPK）磷酸化（Thr 172）和PPAR γ共激活因子-1 α（PGC-1 α）的表达。在体外，我们发现AMPK的敲低或使用AMPK拮抗剂抑制了FGF 21介导的PPAR γ表达的上调，并且KLB的敲低抑制了PPAR γ介导的FGF 21表达的上调。这些结果表明，FGF 21在抑制HPH中发挥保护作用。FGF 21和PPAR γ通过AMPK/PGC-1 α途径和KLB蛋白相互促进彼此在HPH中的表达。
Fibroblast growth factor 21 (FGF21), a primarily liver-derived endocrine factor, has the beneficial effect of protecting blood vessels. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a ligand-activated nuclear transcription factor, has been reported to effectively inhibit pulmonary hypertension (PH). The purpose of this study is to investigate the role of FGF21 in hypoxia-induced PH (HPH) and explore the relationship between FGF21 and PPAR gamma in this disorder. Adult C57BL/6 mice were subjected to four weeks of hypoxia to establish a PH model. The effects of FGF21 and PPAR gamma agonists and antagonists were investigated in HPH mice, as well as the relationship between FGF21 and PPAR gamma in this model. Moreover, we investigated the underlying mechanisms of this relationship between FGF21 and PPAR gamma in vivo and in vitro. In vivo, we found that hypoxia resulted in pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial remodeling, and pulmonary arterial collagen deposition. Furthermore, hypoxia decreased FGF21 and PPAR gamma levels. These changes were reversed by exogenous FGF21 and a PPAR gamma agonist and were further enhanced by a PPAR gamma antagonist. The hypoxia-induced decrease in beta-klotho (KLB) expression was improved by the PPAR gamma agonist and further reduced by the PPAR gamma antagonist. Exogenous FGF21 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) and PPAR gamma coactivator-1 alpha (PGC-1 alpha) expression in PH mouse lung homogenates. In vitro, we found that knockdown of AMPK or using an AMPK antagonist inhibited the FGF21-mediated up-regulation of PPAR gamma expression, and the PPAR gamma-mediated up-regulation of FGF21 expression was inhibited by knockdown of KLB. These results indicated that FGF21 exerts protective effects in inhibiting HPH. FGF21 and PPAR gamma mutually promote each other's expression in HPH via the AMPK/PGC-1 alpha pathway and KLB protein.