Quercetin reverses experimental pulmonary arterial hypertension by modulating the TrkA pathway
Quercetin reverses experimental pulmonary arterial hypertension by modulating the TrkA pathway
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槲皮素通过调节 TrkA 通路逆转实验性肺动脉高压
DOI：
10.1016/j.yexcr.2015.10.013
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发表时间：
2015-11-15
影响因子：
3.7
通讯作者：
Shi, Jing
中科院分区：
文献类型：
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作者：
He, Yuanzhou;Cao, Xiaopei;Shi, Jing
肺动脉高压（PAH）的特征是肺动脉平滑肌细胞（PASMCs）过度增殖、抗凋亡和迁移增加。我们假设槲皮素对这种疾病发挥保护作用，因此，使用雄性Sprague-Dawley大鼠产生PAH的慢性缺氧模型，用槲皮素治疗。在该模型中，槲皮素可预防暴露于缺氧后PAH、右心室肥大和血管重塑的发展。槲皮素在体内可抑制PASMC增殖，促进PASMC凋亡。槲皮素在体外能显著抑制低氧诱导的PASMC增殖，使细胞阻滞于G1/G 0期，并呈剂量依赖性地抑制细胞迁移。此外，我们的研究结果表明，槲皮素增加细胞周期蛋白D1的蛋白水平和细胞周期蛋白B1和Cdc 2的蛋白表达下降。此外，槲皮素改变了Bax/Bcl-2比值，并降低了MMP 2、MMP 9、CXCR 4、整合素β 1和整合素α 5的表达。利用全基因组微阵列分析，我们发现调节增殖、凋亡、细胞周期和迁移的因子与酪氨酸受体激酶A（TrkA）通路有关。此外，槲皮素以剂量依赖性方式抑制缺氧时TrkA/AKT信号级联的激活。此外，槲皮素单独抑制TrkA/AKT信号通路，导致PASMC迁移减少，细胞周期阻滞和诱导凋亡。我们的数据表明，槲皮素是一个潜在的候选人缺氧诱导的PAH的治疗。(C)2015 Elsevier Inc. All rights reserved.
Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation, resistance to apoptosis, and increased migration of pulmonary artery smooth muscle cells (PASMCs). We hypothesized that quercetin exerts protective effects against this disease; thus, a chronic hypoxia model of PAH was generated using male Sprague-Dawley rats, which were treated with quercetin. In this model, quercetin prevented the development of PAH, right ventricular hypertrophy, and vascular remodeling after exposure to hypoxia. Quercetin inhibited PASMC proliferation and increased the apoptosis of PASMCs in vivo. In vitro, quercetin significantly inhibited hypoxia-induced PASMC proliferation, arrested cells in G1/G0 and inhibited cell migration in a dose-dependent manner. Moreover, our results showed that quercetin increased cyclin D1 protein levels and decreased the protein expression of cyclin B1 and Cdc2. Additionally, quercetin altered the Bax/Bcl-2 ratio and reduced MMP2, MMP9, CXCR4, integrin beta 1, and integrin alpha 5 expression. Using genome-wide microarray analysis, we found that factors regulating proliferation, apoptosis, cell cycle, and migration were related to the tyrosine receptor kinase A (TrkA) pathway. In addition, activation of the TrkA/AKT signaling cascade during hypoxia was inhibited by quercetin in a dose-dependent manner. Moreover, quercetin alone inhibited the TrkA/AKT signaling pathway, resulting in decreased PASMC migration, cell cycle arrest and the induction of apoptosis. Our data suggest that quercetin is a potential candidate for the treatment of hypoxia-induced PAH. (C) 2015 Elsevier Inc. All rights reserved.