Key result
Pharmacological inhibition of PFKFB3 by 3PO attenuated cardiac fibrosis and improved left ventricular ejection fraction from 36.24% to 57.58% in post-myocardial infarction mice.
Why the study?
Metabolic reprogramming contributes to cardiac fibroblast activation and post-myocardial infarction cardiac fibrosis, but the underlying mechanisms remain incompletely understood.
Does inhibition of PFKFB3-involved glycolysis alleviate post-myocardial infarction cardiac fibrosis in mice?
Does inhibition of PFKFB3-involved glycolysis alleviate post-myocardial infarction cardiac fibrosis in mice?
Absolute Event Rate: 57.58% vs 36.24%
p-value: p=<0.05
Inhibition of PFKFB3-driven glycolysis attenuates cardiac fibroblast activation and post-myocardial infarction cardiac fibrosis, suggesting a potential therapeutic target for ischemic heart disease.
PFKFB3 inhibition merits further preclinical testing in cardiac remodeling; leaves open translation to human ischemic heart disease.
Metabolic dysregulations have emerged as a major mediator of cardiovascular disorders and fibrotic diseases. Metabolic reprogramming contributes a lot to cardiac fibroblast activation and cardiac fibrosis post-myocardial infarction (MI), yet the mechanism remains incompletely understood. Our work aimed to determine whether or not glycolytic reprogramming, regulated by phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3), is a therapeutic target for alleviating post-MI cardiac fibrosis. Here, we showed that cardiac fibroblasts displayed cell energy phenotype toward augmented glycolysis in response to transforming growth factor-beta 1 (TGF-β1), evidenced by significant extracellular acidification rate (ECAR) increase and lactate accumulation. The expression of glycolytic enzyme PFKFB3, a master activator of glycolysis, was up-regulated in TGF-β1-treated cardiac fibroblasts and in cardiac fibroblasts of post-MI mice. Pharmacological inhibition of PFKFB3 by 3PO diminished TGF-β1-mediated profibrotic phenotypes, attenuated cardiac fibrosis, and preserved cardiac functions in post-MI mice. Meanwhile, the genetic inhibition of PFKFB3 decreased the cardiac fibroblast activation and reversed the differentiated phenotypes in vitro and in vivo. Mechanistically, we identified deubiquitinase OTUD4 as a new binding protein of PFKFB3, and their interaction blocked PFKFB3 degradation via OTUD4-mediated deubiquitylation. Taken together, this work characterized a key role for PFKFB3 in cardiac fibroblast activation and suggested that inhibiting PFKFB3-involved glycolysis is an alternative way to alleviate post-MI cardiac fibrosis. KEY MESSAGES: PFKFB3, a master activator of glycolysis, was highly expressed in ischemic cardiac fibroblasts to enhance cardiac fibrosis The deubiquitinase OTUD4 was identified as a new binding protein of PFKFB3 TGF-β1 blunted the ubiquitination-mediated degradation of PFKFB3 via OTUD4-mediated deubiquitylation Blockade of PFKFB3 contributed to ameliorating ischemia-induced cardiac fibrosis.
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Wang et al. (2023) studied Cardiac fibrosis post-myocardial infarction. 3PO (PFKFB3 inhibitor) vs. Vehicle (DMSO) was evaluated on Left ventricular ejection fraction (%) (p=<0.05). Pharmacological inhibition of PFKFB3 by 3PO attenuated cardiac fibrosis and improved left ventricular ejection fraction from 36.24% to 57.58% in post-myocardial infarction mice.
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