PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension
PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension
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DOI：
10.1073/pnas.1821401116
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发表时间：
2019-07-02
影响因子：
11.1
通讯作者：
Huo, Yuqing
中科院分区：
文献类型：
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作者：
Cao, Yapeng;Zhang, Xiaoyu;Huo, Yuqing
肺血管系统中糖酵解的增加与肺动脉高压（PH）的发生有关。因此，我们研究了糖酵解调节剂 6-磷酸果糖-2-激酶/果糖-2, 6-双磷酸酶 (PFKFB3) 介导的内皮糖酵解是否在 PH 的发展中发挥关键作用。 Pfkfb3 的杂合整体缺乏可保护小鼠免受缺氧诱导的 PH 的影响，而在 Sugen 5416/缺氧治疗的大鼠中，给予 PFKFB3 抑制剂 3PO 几乎完全预防了 PH，表明 PFKFB3 在 PH 的发生中起致病作用。肺切片的免疫染色和分离的肺内皮细胞的蛋白质印迹显示，患有 PH 的啮齿动物和人类的肺内皮细胞中 PFKFB3 表达和活性显着增加。我们培育了内皮 Pfkfb3 组成性或诱导性缺陷的小鼠，并发现这些小鼠无法发生 PH 或表现出 PH 进展缓慢。与对照小鼠相比，内皮 Pfkfb3 敲除小鼠的血管平滑肌细胞增殖、内皮炎症和肺部白细胞募集的严重程度较轻。在缺乏 PFKFB3 的情况下，来自患有 PH 的啮齿动物和人类的肺内皮细胞产生较低水平的生长因子（如 PDGFB 和 FGF2）和促炎因子（如 CXCL12 和 IL1 beta）。这在机制上与 PFKFB3 敲低后肺 EC 中 HIF2A 水平的降低有关。综上所述，这些结果表明靶向 PFKFB3 是治疗 PH 的一种有前途的策略。
Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of Pfkfb3 protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial Pfkfb3 and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial Pfkfb3-knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3, lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1 beta). This is mechanistically linked to decreased levels of HIF2A in lung ECs following PFKFB3 knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.