Investigative ophthalmology & visual science · 2025
Conformational Dynamics of PKM2 Regulate Hypoxia-Induced Pathological Retinal Angiogenesis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zhu Peiwen, Chang Hao, Yang Qian, Chen Wenwen, Chang Qing
Аннотация
PURPOSE: Because anti-vascular endothelial growth factor therapies have limited effect in some cases of retinal neovascularization, there might be other potential pathways involved. Pyruvate kinase M2 (PKM2), a major isoform of pyruvate kinase in tumor cell and human retina, has been broadly studied in oncology and believed to play key roles in tumor growth and invasion. However, its role in retinal angiogenesis remains unclear. In this study, we aimed to explore the contribution of PKM2 conformational dynamics on pathological neovascularization of the retina.
METHODS: We used the oxygen-induced retinopathy (OIR) mouse model and the hypoxia-exposed human retinal microvascular endothelial cell (HRMEC) model to evaluate PKM2 conformational dynamics. DASA-58, a small-molecule activator that increase formation of tetrameric PKM2, was used to evaluate the effects of PKM2 tetramerization.
RESULTS: Hypoxia induced phosphorylation-dependent monomerization of PKM2. The monomer translocated to the nucleus, where it interacted with hypoxia-inducible factor-1α (HIF-1α) to promote angiogenic and glycolytic gene expression. In vitro, treatment with DASA-58 induced the formation of tetrameric PKM2 and prevented its nuclear translocation, which further led to suppressed HIF-1α signaling, reduced glycolysis, and inhibited retinal neovascularization. Pyruvate dehydrogenase kinase 1 (PDHK1) was identified as an upstream modulator of PKM2 phosphorylation. In vivo, DASA-58 treatment led to the reduction in neovascularization, vascular leakage, and preserved retinal thickness, and improved visual function in OIR mice.
CONCLUSIONS: PKM2 conformational dynamics represents a novel regulatory mechanism of hypoxia-induced retinal neovascularization. Transformation of PKM2 tetramers induced by DASA-58 may provide a sound therapeutic approach for neovascular diseases including retinopathy of prematurity (ROP).
METHODS: We used the oxygen-induced retinopathy (OIR) mouse model and the hypoxia-exposed human retinal microvascular endothelial cell (HRMEC) model to evaluate PKM2 conformational dynamics. DASA-58, a small-molecule activator that increase formation of tetrameric PKM2, was used to evaluate the effects of PKM2 tetramerization.
RESULTS: Hypoxia induced phosphorylation-dependent monomerization of PKM2. The monomer translocated to the nucleus, where it interacted with hypoxia-inducible factor-1α (HIF-1α) to promote angiogenic and glycolytic gene expression. In vitro, treatment with DASA-58 induced the formation of tetrameric PKM2 and prevented its nuclear translocation, which further led to suppressed HIF-1α signaling, reduced glycolysis, and inhibited retinal neovascularization. Pyruvate dehydrogenase kinase 1 (PDHK1) was identified as an upstream modulator of PKM2 phosphorylation. In vivo, DASA-58 treatment led to the reduction in neovascularization, vascular leakage, and preserved retinal thickness, and improved visual function in OIR mice.
CONCLUSIONS: PKM2 conformational dynamics represents a novel regulatory mechanism of hypoxia-induced retinal neovascularization. Transformation of PKM2 tetramers induced by DASA-58 may provide a sound therapeutic approach for neovascular diseases including retinopathy of prematurity (ROP).