Evaluation of Naturally Occurring HIF-1 Inhibitors for Pulmonary Arterial Hypertension
Evaluation of Naturally Occurring HIF-1 Inhibitors for Pulmonary Arterial Hypertension
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DOI：
10.1002/cbic.202100223
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发表时间：
2021-07-09
期刊：
影响因子：
3.2
通讯作者：
Ishibashi, Masami
中科院分区：
文献类型：
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作者：
Arai, Midori A.;Sakuraba, Kota;Ishibashi, Masami
肺动脉高压（PAH）是一种罕见且严重的进行性疾病，其特征为肺动脉高压。慢性缺氧引起代谢紊乱和肺动脉平滑肌细胞（PASMCs）的Warburg效应。丙酮酸脱氢酶激酶1 （PDK1）是缺氧诱导因子（HIF-1）增加Warburg效应的关键酶。我们构建了一个基于细胞的HIF-1抑制剂荧光素酶检测系统。使用该系统，鉴定了6种HIF-1抑制剂。在这些抑制剂中，研究了他吉宁C(1)对PASMC的作用。他吉宁C(1)明显降低HIF-1 β和HIF-1靶点PDK1的量。这一结果表明HIF-1抑制剂有效降低PDK1活性，这是pasmc中代谢紊乱和Warburg效应的一个原因。鉴定天然存在的HIF-1抑制剂可以为开发多环芳烃药物提供新的见解。
Pulmonary arterial hypertension (PAH) is a rare and severe progressive disorder characterized by high pulmonary artery pressure. Chronic hypoxia causes a metabolic disorder and the Warburg effect in pulmonary arterial smooth muscle cells (PASMCs). Pyruvate dehydrogenase kinase 1 (PDK1) is a key enzyme in Warburg effect increased by hypoxia-inducible factor (HIF-1). We constructed a cell-based luciferase assay system for HIF-1 inhibitors. Using this system, six HIF-1 inhibitors were identified. Among these inhibitors, the effect of tagitinin C (1) on PASMC was investigated. Tagitinin C (1) clearly decreased the amount of HIF-1 beta and the HIF-1 target PDK1. This result indicates that HIF-1 inhibitors effectively decrease PDK1 activity, which is a cause of the metabolic disorder and Warburg effect observed in PASMCs. Identifying naturally occurring HIF-1 inhibitors could provide novel insights into the development of PAH medications.