3-Bromopyruvate reverses hypoxia-induced pulmonary arterial hypertension through inhibiting glycolysis: In vitro and in vivo studies
3-Bromopyruvate reverses hypoxia-induced pulmonary arterial hypertension through inhibiting glycolysis: In vitro and in vivo studies
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DOI：
10.1016/j.ijcard.2018.03.104
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发表时间：
2018-09-01
影响因子：
3.5
通讯作者：
Yuan, Linbo
中科院分区：
文献类型：
--
作者：
Chen, Fangzheng;Wang, Heng;Yuan, Linbo
背景：肺动脉平滑肌细胞（PASMC）增殖对于肺动脉高压（PAH）发病机制中的肺血管重塑至关重要，抑制PASMC代谢可能成为逆转这一过程的新疗法。 3-溴丙酮酸 (3-BrPA) 是一种有效的糖酵解抑制剂，但其对 PAH 的作用尚不清楚。本研究旨在评价3-BrPA对PAH大鼠的治疗作用，并探讨3-BrPA在PASMC增殖和凋亡中的可能机制。方法：将27只健康SD大鼠分组，给予缺氧/常氧和3-BrPA/生理盐水治疗。测量平均肺动脉压（mPAP）和心输出量（CO）并计算肺血管阻力（PVR）。计算右心室肥厚指数（RVHI）以评估右心室肥厚程度。通过图像分析测量内侧壁面积百分比（WA%）和内侧壁厚度（WT%）。 PASMCs组接受缺氧/常氧治疗和3-BrPA/生理盐水。通过CCK-8和细胞划痕实验分别检测PASMC的增殖和迁移。采用Western Blotting和乳酸检测试剂盒分别测定己糖激酶II（HK-2）表达和乳酸水平，检测糖酵解。结果：缺氧处理后大鼠mPAP、PVR、PVHI、WA%和WT%升高，但低于缺氧环境下接受3-BrPA的大鼠。缺氧处理后PASMCs中HK-2表达、乳酸浓度、OD值和划痕面积增加，而给予3-BrPA后则减少。结论：3-BrPA可以通过抑制糖酵解来抑制PASMC增殖和迁移，并能有效逆转缺氧所致PAH大鼠的血管重塑。 (c) 2018 年由 Elsevier B.V. 出版
Background: Pulmonary arterial smooth muscle cell (PASMC) proliferation is vital to pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) pathogenesis, and inhibiting PASMC metabolismcould serve as a new possible therapy to reverse the process. 3-Bromopyruvate (3-BrPA) is an effective glycolysis inhibitor with its effect in PAH remains unclear. Our study aims to assess the therapeutic effect of 3-BrPA in PAH rats and investigate the possible mechanism of 3-BrPA in PASMC proliferation and apoptosis.Methods: 27 healthy SD rats were grouped and treated with hypoxia/normoxia and administration of 3-BrPA/physiological saline. Mean pulmonary artery pressure (mPAP) and cardiac output (CO) were measured and pulmonary vascular resistance (PVR) was calculated. Right ventricular hypertrophy index (RVHI) was calculated to evaluate the right ventricular hypertrophy degree. The percentage of medial wall area (WA%) and medial wall thickness (WT%) were measured by image analysis. PASMCs groups received hypoxia/normoxia treatments and 3-BrPA/physiological saline. PASMC proliferation and migration were respectively detected by CCK-8 and cell wound scratch assay. Hexokinase II (HK-2) expression and lactate level were respectively measured by Western Blotting and lactate test kit to detect glycolysis.Results: mPAP, PVR, PVHI, WA% and WT% in rats increased after the hypoxia treatment, but were lower compared to rats received 3-BrPA in hypoxia environment. HK-2 expression, lactate concentration, OD value and scratch areas in PASMCs increased after the hypoxia treatment, but were decreased after the administration of 3-BrPA.Conclusion: 3-BrPA can inhibit PASMC proliferation and migration by inhibiting glycolysis, and is effective in reversing the vascular remodeling in hypoxia-induced PAH rats. (c) 2018 Published by Elsevier B.V.