Key result
Inhibiting PFKFB3 or Nox1 restores endothelium-dependent relaxation in diabetic mice by blocking excess glycolysis.
Why the study?
Whether endothelial cell glycolysis regulates vascular tone and contributes to impaired endothelium-dependent relaxation in type 1 diabetes remains unknown.
Excess endothelial cell glycolysis mediated by methylglyoxal, HIF1α, and PFKFB3 is a novel mechanism driving endothelial dysfunction in Type 1 diabetes.
Should not change clinical practice; leaves open whether PFKFB3 inhibition improves endothelial function in human diabetes.
BACKGROUND: Type 1 diabetes (T1D) is a major cause of endothelial dysfunction. Although cellular bioenergetics has been identified as a new regulator of vascular function, whether glycolysis, the primary bioenergetic pathway in endothelial cells (EC), regulates vascular tone and contributes to impaired endothelium-dependent relaxation (EDR) in T1D remains unknown. METHODS: Experiments were conducted in Akita mice with intact or selective deficiency in EC PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), the main regulator of glycolysis. Seahorse analyzer and myography were employed to measure glycolysis and mitochondrial respiration, and EDR, respectively, in aortic explants. EC PFKFB3 (Ad-PFKFB3) and glycolysis (Ad-GlycoHi) were increased in situ via adenoviral transduction. RESULTS: T1D increased EC glycolysis and elevated EC expression of PFKFB3 and NADPH oxidase Nox1 (NADPH oxidase homolog 1). Functionally, pharmacological and genetic inhibition of PFKFB3 restored EDR in T1D, while in situ aorta EC transduction with Ad-PFKFB3 or Ad-GlycoHi reproduced the impaired EDR associated with T1D. Nox1 inhibition restored EDR in aortic rings from Akita mice, as well as in Ad-PFKFB3-transduced aorta EC and lactate-treated wild-type aortas. T1D increased the expression of the advanced glycation end product precursor methylglyoxal in the aortas. Exposure of the aortas to methylglyoxal impaired EDR, which was prevented by PFKFB3 inhibition. T1D and exposure to methylglyoxal increased EC expression of HIF1α (hypoxia-inducible factor 1α), whose inhibition blunted methylglyoxal-mediated EC PFKFB3 upregulation. CONCLUSIONS: EC bioenergetics, namely glycolysis, is a new regulator of vasomotion and excess glycolysis, a novel mechanism of endothelial dysfunction in T1D. We introduce excess methylglyoxal, HIF1α, and PFKFB3 as major effectors in T1D-mediated increased EC glycolysis.
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Atawia et al. (2023) studied Type 1 diabetes. Pharmacological and genetic inhibition of PFKFB3 or Nox1 vs. Untreated T1D mice was evaluated on Endothelium-dependent relaxation (EDR) and EC glycolysis. Pharmacological and genetic inhibition of PFKFB3 or Nox1 restored endothelium-dependent relaxation in Type 1 diabetic mice, identifying excess glycolysis as a mechanism of endothelial dysfunction.