3-Bromopyruvate Attenuates Experimental Pulmonary Hypertension via Inhibition of Glycolysis
3-Bromopyruvate Attenuates Experimental Pulmonary Hypertension via Inhibition of Glycolysis
复制标题
DOI：
10.1093/ajh/hpy191
复制
发表时间：
2018-12
影响因子：
3.2
通讯作者：
Yun-Long Zhang;Rui Zhang;Yi Shen;Kaifeng Huang;Yangyang He;Jun-Han Zhao;Z. Jing
中科院分区：
文献类型：
--
作者：
Yun-Long Zhang;Rui Zhang;Yi Shen;Kaifeng Huang;Yangyang He;Jun-Han Zhao;Z. Jing
背景代谢从线粒体氧化磷酸化转变为糖酵解和己糖激酶的线粒体结合配偶体是癌症的共同特征。这些也出现在肺动脉高压（PH）中。小分子 3-溴丙酮酸 (3-BrPA) 是己糖激酶 2 (HK 2) 的抑制剂，是一种非常强大且快速起效的抗癌剂。然而，这是否会对希盟带来潜在好处仍不得而知。方法 野百合碱 (MCT) 诱导的 PH 的 Sprague-Dawley 大鼠口服 2 剂 3-BrPA（分别为 15 和 30 mg/kg/天），持续 14 天。通过右心导管插入术获得血流动力学参数。进行组织病理学、免疫组织化学、透射电子显微镜、流式细胞术和相对蛋白表达的评估。结果与MCT治疗相比，3-BrPA降低了平均肺动脉压和肺血管阻力，并增加了心输出量。 3-BrPA 除了增强肺动脉平滑肌细胞凋亡、减弱小肺动脉重塑和右心室肥厚之外，还显着抑制增殖。 3-BrPA 治疗显着降低了线粒体膜电位并恢复了线粒体结构。此外，3-BrPA 显着抑制 HK 2 表达，但不抑制 HK 1。3-BrPA 给药后，丙酮酸脱氢酶激酶和乳酸脱氢酶的表达均降低，而丙酮酸脱氢酶和胞质细胞色素 c 的表达上调。结论 这项研究表明 3-BrPA 逆转 PH 与糖酵解的改变和线粒体功能的改善有关，表明“代谢靶向”是 PH 的合理治疗策略。
BACKGROUND The shift of metabolism from mitochondrial oxidative phosphorylation to glycolysis and mitochondria binding partner of hexokinase are features common to cancer. These have been seen in pulmonary hypertension (PH) as well. An inhibitor of hexokinase 2 (HK 2), the small molecule 3-bromopyruvate (3-BrPA) is an incredibly powerful and swift-acting anticancer agent. However, whether it could be of potential benefit to PH has still been unknown. METHODS Sprague-Dawley rats with monocrotaline (MCT)-induced PH were administered 2 oral doses of 3-BrPA (15 and 30 mg/kg/day, respectively) for 14 days. Hemodynamic parameters were obtained by right heart catheterization. Histopathology, immunohistochemistry, transmission electron microscopy, flow cytometry, and assessments of relative protein expressions were conducted. RESULTS Compared with MCT treatment, 3-BrPA decreased mean pulmonary arterial pressure and pulmonary vascular resistance, and increased cardiac output. 3-BrPA significantly suppressed proliferation in addition to enhancing apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodeling and right ventricular hypertrophy. Treatment with 3-BrPA markedly reduced the mitochondrial membrane potential and restored mitochondrial structure. Furthermore, 3-BrPA significantly inhibited HK 2 expression but not HK 1. The expression of both pyruvate dehydrogenase kinase and lactate dehydrogenase was decreased whereas that of pyruvate dehydrogenase and cytosolic cytochrome c was upregulated with 3-BrPA administration. CONCLUSION This study demonstrates the reversal of PH by 3-BrPA is related to alteration in glycolysis and improved mitochondria function, indicating the "metabolic targeting" as a rational therapeutic strategy for PH.