KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells

Area of Science:

• Cardiovascular Biology
• Cellular Metabolism
• Molecular Biology

Background:

• Vascular smooth muscle cells (VSMCs) change phenotype in atherosclerosis.
• KLF4 influences VSMC phenotypic switching, but its role in metabolic regulation is unclear.

Purpose of the Study:

• To investigate how KLF4 links metabolic shifts, specifically glycolysis, to VSMC phenotypic transitions in atherosclerosis.
• To elucidate the molecular mechanisms underlying KLF4-mediated glycolytic regulation.

Main Methods:

• Analysis of KLF4 expression in atherosclerotic lesions.
• Investigating the effect of KLF4 on glycolysis and PFKFB3 expression.
• Assessing the role of glycolysis inhibition in KLF4-induced VSMC switching.
• Identifying downstream targets of KLF4, including circCTDP1 and eEF1A2.
• Examining the impact of TMAO on KLF4, glycolysis, and VSMC phenotype.

Main Results:

• KLF4 upregulation correlates with VSMC phenotypic switching in atherosclerosis.
• KLF4 promotes a metabolic switch to glycolysis by increasing PFKFB3 expression.
• Inhibition of glycolysis blocks KLF4-induced VSMC phenotypic switching.
• KLF4 upregulates circCTDP1 and eEF1A2, which cooperatively enhance PFKFB3 expression.
• TMAO induces VSMC glycolytic shift and phenotypic switching via KLF4 upregulation.

Conclusions:

• KLF4 is a key mediator linking glycolytic switch to VSMC phenotypic transitions.
• A novel KLF4-eEF1A2/circCTDP1-PFKFB3 axis is crucial for VSMC phenotypic switching in atherosclerosis.
• Targeting this pathway may offer therapeutic strategies for atherosclerosis.