Lactate Promotes Endothelial-Mesenchymal Transition via Mediating Twist1 Lactylation in Hypoxic Pulmonary Hypertension - PubMed
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- #lactate
- #pulmonary hypertension
- #EndoMT
- Elevated plasma lactate is a significant risk factor in pulmonary hypertension (PH).
- Endothelial-mesenchymal transition (EndoMT) is a major contributor to PH pathology.
- Modulating lactate levels critically influences PH progression in both in vivo and in vitro models.
- Inhibition of lactate production ameliorated hemodynamic and vascular remodeling in hypoxic PH mice.
- Exogenous lactate exacerbated PH pathologies in the same model.
- Lactate promoted a pro-remodeling phenotype in human pulmonary arterial endothelial cells under hypoxia.
- Lactate enhanced migration, proliferation, and EndoMT in these cells.
- Mechanistically, lactate induced Twist1 lactylation via enhanced association with p300/CBP, promoting its nuclear translocation.
- This upregulated TGFB1 transcription and activated the Smad2 pathway, driving EndoMT.
- Twist1 knockdown abolished the lactate-induced EndoMT effect.
- The study reveals a lactate-Twist1 lactylation-TGFB1 axis promoting vascular remodeling in PH.