Glycoprotein 130 Inhibitor Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats
Glycoprotein 130 Inhibitor Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats
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糖蛋白 130 抑制剂可改善野百合碱诱导的大鼠肺动脉高压
DOI：
10.1016/j.cjca.2016.02.058
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发表时间：
2016-11-01
影响因子：
6.2
通讯作者：
Tang, Yi
中科院分区：
文献类型：
--
作者：
Huang, Zhiwei;Liu, Zhihong;Tang, Yi
背景：肺动脉高压（PAH）的特点是血管收缩、血管重塑和微血栓事件。炎症细胞因子白介素（IL-6）可能是PAH发生的关键因素，而糖蛋白130（Gp130）是IL-6重要的信号转导亚基。我们研究的目的是评估 Gp130 抑制剂在野百合碱 (MCT) 暴露大鼠中减轻炎症和改善 PAH 相关血管重塑的有效性。方法：Sprague-Dawley 大鼠（n = 96；体重 240-250 g）被随机分为 3 组：对照组、MCT 暴露 (MCT) 和 MCT 暴露加 Gp130 抑制剂(MCT-Gp) 从第 14-28 天每天给药 (5 mg/kg)。在第1周至第4周处死每组8只大鼠，在第28天比较各组之间的以下测量变量：血流动力学、右心室肥厚、形态测量、免疫组织化学结果、IL-6水平、磷酸化信号转导器和转录激活剂3、增殖细胞核抗原（PCNA）、骨形态发生蛋白受体2（BMPR2）、促血管生成因子、血管内皮生长因子（VEGF）、增殖激酶细胞外信号调节激酶 (ERK)、生存素、Bcl-2 和 Bax。结果：与 MCT 组相比，MCT 暴露后，Gp130 抑制剂改善了血流动力学，显着降低了炎症的严重程度（根据 IL-6 水平评估）（P < 0.0001），并逆转了肺动脉重塑（根据内壁厚度评估）（P < 0.0001）。 Gp130抑制剂上调MCT暴露肺中BMPR2表达（P=0.040），并降低PCNA、VEGF、ERK和survivin表达（均P<0.05）。结论：Gp130抑制剂上调MCT暴露肺中BMPR2表达，恢复BMPR2/IL-6平衡，减轻IL-6相关炎症，抑制肺动脉平滑肌细胞增殖，并抑制肺动脉平滑肌细胞增殖。改善 MCT 诱导的大鼠 PH 中的肺血管重塑。
Background: Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, vascular remodelling, and microthrombotic events. Inflammatory cytokine interleukin (IL-6) may be a key factor in the development of PAH, and glycoprotein 130 (Gp130) is an important signal-transducing subunit of IL-6. The aim of our study was to evaluate the effectiveness of Gp130 inhibitor in reducing inflammation and ameliorating PAH-related vascular remodelling in monocrotaline (MCT)-exposed rats.Methods: Sprague-Dawley rats (n = 96; weight, 240-250 g) were randomly divided into 3 groups: control, MCT-exposed (MCT), and MCT-exposed plus Gp130 inhibitor (MCT-Gp) administered daily (5 mg/kg) from days 14-28. Eight rats were killed in each group at weeks 1 through 4, with the following measured variables compared across groups on day 28: hemodynamics, right ventricular hypertrophy, morphometric measurements, immunohistochemical results, levels of IL-6, phosphorylated signal transducer and activator of transcription 3, proliferating cell nuclear antigen (PCNA), bone morphogenetic protein receptor-2 (BMPR2), proangiogenic factor, vascular endothelial growth factor (VEGF), proproliferative kinase extracellular signal-regulated kinase (ERK), survivin, Bcl-2, and Bax.Results: Compared with the MCT group, Gp130 inhibitor, after MCT exposure, improved hemodynamics and significantly reduced the severity of inflammation, as estimated by levels of IL-6 (P < 0.0001), and reversed pulmonary arterial remodelling, as assessed by medial wall thickness (P < 0.0001). Gp130 inhibitor upregulated BMPR2 expression in MCT-exposed lungs (P = 0.040) and decreased the expression of PCNA, VEGF, ERK, and survivin (all P < 0.05).Conclusions: Gp130 inhibitor upregulated BMPR2 expression in MCT-exposed lungs, restored the BMPR2/IL-6 balance, reduced IL-6-associated inflammation, inhibited pulmonary artery smooth muscle cell proliferation, and ameliorated pulmonary vascular remodelling in MCT-induced PH in rats.