Phospholysine phosphohistidine inorganic pyrophosphate phosphatase suppresses glycolysis and proliferation of pulmonary artery smooth muscle cells in hypoxic pulmonary hypertension via inhibition of lactate dehydrogenase A

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology Pub Date : 2025-09-20 DOI:10.1016/j.ejphar.2025.178172

Yuhan Qin , Ziqi Sha , Yong Qiao , Gaoliang Yan , Dong Wang , Chengchun Tang

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引用次数: 0

Abstract

Background

Hypoxic pulmonary hypertension (HPH) is a progressive disorder marked by pulmonary vasculature remodeling, primarily driven by the overproliferation of pulmonary artery smooth muscle cells (PASMCs). Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has been identified as a tumor suppressor in cancer. However, its role in the proliferation of PASMCs and its implications in HPH remain unexplored.

Methods

Hypoxia and SU5416 (SuHx) were used to establish HPH rat models. Rat and human PASMCs models with LHPP overexpression and silencing were constructed to evaluate the role of LHPP in HPH. Cell proliferation was assessed using both CCK-8 and EdU assays. LHPP targeting approach (siRNA, adenovirus, and adeno-associated virus AAV) was used for in vitro and in vivo experiments to investigate the impact of LHPP on PASMCs glycolysis. We measured lactate levels, and key glycolytic enzymes, focusing on LHPP's influence on lactate dehydrogenase A (LDHA). Additionally, the effect of methyltransferase-like 3 (METTL3) on the reduction of LHPP expression was examined.

Results

LHPP levels were significantly decreased in both the pulmonary arteries of rats with SuHx-induced HPH and in hypoxia-treated PASMCs. Overexpression of LHPP inhibited the hypoxia-induced increase in proliferation potential and alleviated pulmonary vascular remodeling (PVR) in vivo. Conversely, silencing LHPP promoted PASMCs proliferation. LHPP overexpression suppressed PASMCs glycolysis and proliferation by lactate dehydrogenase A (LDHA)-mediated glycolysis. Mechanistic studies revealed that METTL3 downregulated LHPP expression.

Conclusion

This study emphasizes the METTL3/LHPP/LDHA axis's role in enhancing PASMC proliferation and HPH. LHPP may represent a potential therapeutic target for the treatment of hypoxic pulmonary hypertension.

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磷酸赖氨酸、磷酸组氨酸、无机焦磷酸盐磷酸酶通过抑制乳酸脱氢酶A抑制缺氧肺动脉高压患者肺动脉平滑肌细胞的糖酵解和增殖。

背景：低氧性肺动脉高压（HPH）是一种以肺血管重构为特征的进行性疾病，主要由肺动脉平滑肌细胞（PASMCs）过度增殖引起。磷酸赖氨酸磷组氨酸无机焦磷酸盐磷酸酶（LHPP）已被确定为肿瘤抑制因子。然而，其在PASMCs增殖中的作用及其在HPH中的意义仍未被探索。方法：采用缺氧和SU5416 （SuHx）建立HPH大鼠模型。构建LHPP过表达和沉默的大鼠和人PASMCs模型，评价LHPP在HPH中的作用。用CCK-8和EdU检测细胞增殖。采用LHPP靶向方法（siRNA、腺病毒和腺相关病毒AAV）进行体外和体内实验，研究LHPP对PASMCs糖酵解的影响。我们测量了乳酸水平和关键的糖酵解酶，重点研究了LHPP对乳酸脱氢酶A （LDHA）的影响。此外，我们还检测了甲基转移酶样3 （METTL3）对LHPP表达降低的影响。结果：在suhx诱导的HPH大鼠和缺氧处理的PASMCs中，肺动脉中LHPP水平均显著降低。在体内，LHPP过表达可抑制缺氧诱导的肺细胞增殖潜能升高，减轻肺血管重构（PVR）。相反，沉默LHPP可促进PASMCs的增殖。LHPP过表达抑制PASMCs糖酵解和乳酸脱氢酶A （LDHA）介导的糖酵解增殖。机制研究显示，METTL3下调LHPP的表达。结论：本研究强调了METTL3/LHPP/LDHA轴在促进PASMC增殖和HPH中的作用。LHPP可能是治疗低氧性肺动脉高压的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European journal of pharmacology 医学-药学

CiteScore

9.00

自引率

0.00%

发文量

572

审稿时长

34 days

期刊介绍： The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems. The scope includes: Behavioural pharmacology Neuropharmacology and analgesia Cardiovascular pharmacology Pulmonary, gastrointestinal and urogenital pharmacology Endocrine pharmacology Immunopharmacology and inflammation Molecular and cellular pharmacology Regenerative pharmacology Biologicals and biotherapeutics Translational pharmacology Nutriceutical pharmacology.