PFKFB3-driven vascular smooth muscle cell glycolysis promotes vascular calcification via the altered FoxO3 and lactate production

Jiaxin Chen, Hongjiao Yu, Xiao Tan, Simon Wing Fai Mok, Yuchen Xie, Yueheng Wang, Xueyan Jiang, Vicky E Macrae, Lan Lan, Xiaodong Fu, Dongxing Zhu

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

A link between increased glycolysis and vascular calcification has recently been reported, but it remains unclear how increased glycolysis contributes to vascular calcification. We therefore investigated the role of PFKFB3, a critical enzyme of glycolysis, in vascular calcification. We found that PFKFB3 expression was upregulated in calcified mouse VSMCs and arteries. We showed that expression of miR-26a-5p and miR-26b-5p in calcified mouse arteries was significantly decreased, and a negative correlation between Pfkfb3 mRNA expression and miR-26a-5p or miR-26b-5p was seen in these samples. Overexpression of miR-26a/b-5p significantly inhibited PFKFB3 expression in VSMCs. Intriguingly, pharmacological inhibition of PFKFB3 using PFK15 or knockdown of PFKFB3 ameliorated vascular calcification in vD3 -overloaded mice in vivo or attenuated high phosphate (Pi)-induced VSMC calcification in vitro. Consistently, knockdown of PFKFB3 significantly reduced glycolysis and osteogenic transdifferentiation of VSMCs, whereas overexpression of PFKFB3 in VSMCs induced the opposite effects. RNA-seq analysis and subsequent experiments revealed that silencing of PFKFB3 inhibited FoxO3 expression in VSMCs. Silencing of FoxO3 phenocopied the effects of PFKFB3 depletion on Ocn and Opg expression but not Alpl in VSMCs. Pyruvate or lactate supplementation, the product of glycolysis, reversed the PFKFB3 depletion-mediated effects on ALP activity and OPG protein expression in VSMCs. Our results reveal that blockade of PFKFB3-mediated glycolysis inhibits vascular calcification in vitro and in vivo. Mechanistically, we show that FoxO3 and lactate production are involved in PFKFB3-driven osteogenic transdifferentiation of VSMCs. PFKFB3 may be a promising therapeutic target for the treatment of vascular calcification.

Original languageEnglish
Article numbere23182
Pages (from-to)1-20
Number of pages20
JournalThe FASEB Journal
Volume37
Issue number10
Early online date8 Sept 2023
DOIs
Publication statusPublished - Oct 2023

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Mice
  • Lactic Acid
  • Muscle, Smooth, Vascular
  • Vascular Calcification/genetics
  • Phosphoric Monoester Hydrolases
  • Glycolysis
  • MicroRNAs

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