PFKFB3: A Potential Key to Ocular Angiogenesis

Zhou, Ziyi; Wang, Lin; Wang, Yusheng; Dou, Guo‐Rui

doi:10.3389/fcell.2021.628317

Cited by 11 publications

(10 citation statements)

References 138 publications

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“…PFKFB3-driven glycolysis has been well documented in endothelial pathophysiology, including valve formation, vessel sprouting, etc. 40 – 42 We demonstrate that SAC reverses PFKFB3 induction by promoting its degradation and therefore limits augmented glycolysis and EndoMT. Specific PFKFB3 kinase inhibitors PFK-015, 3PO, and endothelial Pfkfb3 haplodeficiency conformably recapitulate the effects of SAC in suppression of EndoMT in vitro and in vivo, further supporting this rationale.…”

Section: Discussionmentioning

confidence: 79%

Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response

Zeng

Pan

Zhan

et al. 2022

Sig Transduct Target Ther

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Endothelial-to-mesenchymal transition (EndoMT), the process wherein endothelial cells lose endothelial identity and adopt mesenchymal-like phenotypes, constitutes a critical contributor to cardiac fibrosis. The phenotypic plasticity of endothelial cells can be intricately shaped by alteration of metabolic pathways, but how endothelial cells adjust cellular metabolism to drive EndoMT is incompletely understood. Here, we identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) as a critical driver of EndoMT via triggering abnormal glycolysis and compromising mitochondrial respiration. Pharmacological suppression of PFKFB3 with salvianolic acid C (SAC), a phenolic compound derived from Salvia miltiorrhiza, attenuates EndoMT and fibrotic response. PFKFB3-haplodeficiency recapitulates the anti-EndoMT effect of SAC while PFKFB3-overexpression augments the magnitude of EndoMT and exacerbates cardiac fibrosis. Mechanistically, PFKFB3-driven glycolysis compromises cytoplasmic nicotinamide adenine dinucleotide phosphate (reduced form, NADPH) production via hijacking glucose flux from pentose phosphate pathway. Efflux of mitochondrial NADPH through isocitrate/α-ketoglutarate shuttle replenishes cytoplasmic NADPH pool but meanwhile impairs mitochondrial respiration by hampering mitochondrial iron-sulfur cluster biosynthesis. SAC disrupts PFKFB3 stability by accelerating its degradation and thus maintains metabolic homeostasis in endothelial cells, underlying its anti-EndoMT effects. These findings for the first time identify the critical role of PFKFB3 in triggering EndoMT by driving abnormal glycolysis in endothelial cells, and also highlight the therapeutic potential for pharmacological intervention of PFKFB3 (with SAC or other PFKFB3 inhibitors) to combat EndoMT-associated fibrotic responses via metabolic regulation.

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Section: Discussionmentioning

confidence: 79%

Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response

Zeng

Pan

Zhan

et al. 2022

Sig Transduct Target Ther

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“…PFKFB3 has been shown to be widely expressed in different tissues and organs and to play an important role in regulating angiogenesis [ 23 , 24 ]. Therefore, we hypothesized that the targeted delivery of PFKFB3 to the placenta would promote angiogenesis and thus enhance placental function, and that an increased placental weight would lead to a corresponding increase in fetal weight.…”

Section: Resultsmentioning

confidence: 99%

“…In recent years, PFKFB3, a key regulator of glycolysis, has been shown to play an increasingly important role in regulating angiogenesis through metabolic pathways independent of genetic signals [ 14 , 24 ]. De Bock et al [ 10 ] showed that PFKFB3-mediated glycolysis could directly regulate vascular sprouting and promote angiogenesis, and that inactivation of the PFKFB3 gene could inhibit angiogenesis in mice [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Placenta-Targeted Nanoparticles Loaded with PFKFB3 Overexpression Plasmids Enhance Angiogenesis and Placental Function

Liu

et al. 2022

Bioengineering

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Placental angiogenesis disorder and placental dysplasia are important causes of many pregnancy complications. Due to safety and economic benefits, effective treatment strategies are currently limited. PFKFB3 is a key regulator of glycolysis that controls angiogenesis through a metabolic pathway independent of genetic signals. In this study, we constructed the nanodrug T-NPPFKFB3 and explored its feasibility to promote angiogenesis and enhance placental function. First, liposomes containing PFKFB3 overexpression plasmids modified by the placental homing peptide CGKRK were synthesized by the thin film method. In vivo experiments revealed that T-NPPFKFB3 injected intravenously specifically accumulated in the mouse placenta and therein upregulated the expression of PFKFB3 without affecting its expression in other important organs. In addition, T-NPPFKFB3 promoted placental angiogenesis and increased the fetal and placental weights of the mice. Finally, we evaluated the safety of T-NPPFKFB3. The expression levels of ALS/AST/BUN in the sera of pregnant mice were not significantly different from those in the sera of control group mice. However, T-NPPFKFB3 did not cause obvious fetal abnormalities or alter the average litter size. In conclusion, T-NPPFKFB3 can specifically target the placenta, promote angiogenesis, and enhance placental function without obvious side effects. Therefore, it has potential as a new strategy for the treatment of pregnancy complications.

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“…In renal cell carcinoma, PFKFB3 knockout inhibits glycolysis and cell proliferation, suggesting that PFKFB3 could be used as a potential therapeutic target ( 83 ). Emerging evidence has shown that PFKFB3 also plays an important role in regulating physiological and pathological angiogenesis ( 84 ). Endothelial proliferation depends on glycolysis: 85% of ATP is produced by converting glucose into lactate, and pharmacological inhibition of PFKFB3 damages the development of the mouse retinal vascular system ( 85 ).…”

Section: The Regulatory Mechanism Of Hif-1α In Renal Fibrosismentioning

confidence: 99%

Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis

et al. 2022

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Renal fibrosis is the result of renal tissue damage and repair response disorders. If fibrosis is not effectively blocked, it causes loss of renal function, leading to chronic renal failure. Metabolic reprogramming, which promotes cell proliferation by regulating cellular energy metabolism, is considered a unique tumor cell marker. The transition from oxidative phosphorylation to aerobic glycolysis is a major feature of renal fibrosis. Hypoxia-inducible factor-1 α (HIF-1α), a vital transcription factor, senses oxygen status, induces adaptive changes in cell metabolism, and plays an important role in renal fibrosis and glucose metabolism. This review focuses on the regulation of proteins related to aerobic glycolysis by HIF-1α and attempts to elucidate the possible regulatory mechanism underlying the effects of HIF-1α on glucose metabolism during renal fibrosis, aiming to provide new ideas for targeted metabolic pathway intervention in renal fibrosis.

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PFKFB3: A Potential Key to Ocular Angiogenesis

Cited by 11 publications

References 138 publications

Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response

Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response

Placenta-Targeted Nanoparticles Loaded with PFKFB3 Overexpression Plasmids Enhance Angiogenesis and Placental Function

Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis

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