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

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.