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The P4HA1/HIF1α feedback loop modulates endothelial dysfunction in pulmonary hypertension.

Yunwei Chen1, Yifei Lv1, Meng Yang1

  • 1Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

Respiratory Research
|November 22, 2025
PubMed
Summary
This summary is machine-generated.

The glycolytic protein P4HA1 is upregulated in pulmonary hypertension (PH). Targeting the P4HA1/HIF1α pathway may offer a new therapeutic strategy for treating PH and its associated vascular remodeling.

Keywords:
Endothelial cellsGlycolysisHIF1αP4HA1Pulmonary hypertension

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Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Cellular Metabolism

Background:

  • Pulmonary hypertension (PH) is a severe vascular disease leading to right heart failure.
  • The role of the glycolytic protein P4HA1 in PH pathogenesis is not well understood.

Purpose of the Study:

  • To investigate the role of P4HA1 in the pathogenesis of pulmonary hypertension.
  • To elucidate the P4HA1/HIF1α signaling axis in hypoxia-induced pulmonary vascular remodeling.

Main Methods:

  • RNA-sequencing of hypoxic human pulmonary artery endothelial cells (HPAECs).
  • In vitro knockdown of P4HA1 to assess effects on glycolysis, proliferation, and migration.
  • Mechanistic studies on HIF1α regulation and P4HA1-mediated stabilization.
  • In vivo assessment using AAV9-shP4HA1 in a mouse PH model.

Main Results:

  • P4HA1 is upregulated in HPAECs under hypoxia, transcriptionally activated by HIF1α.
  • P4HA1 stabilizes HIF1α, creating a self-amplifying loop.
  • P4HA1 knockdown suppressed hypoxia-induced glycolysis, proliferation, and migration in HPAECs.
  • Endothelial-specific P4HA1 knockdown attenuated pulmonary vascular remodeling and improved right ventricular function in vivo.

Conclusions:

  • P4HA1 is a novel contributor to PH pathogenesis.
  • Targeting the P4HA1/HIF1α axis presents a potential therapeutic strategy for pulmonary hypertension.