Increased PFKFB3 expression in endothelial cells from obese models decreases NO production and enhances NOX1/NOX5 activities, linking altered metabolism to endothelial dysfunction.
PFKFB3 links altered glycolytic metabolism to endothelial dysfunction in obesity and T2D by disrupting the balance between NO production and ROS generation.
Obesity and type 2 diabetes (T2D) increase cardiovascular risk, largely due to altered metabolic state. An early consequence of T2D/obesity is the loss of endothelial function and impaired nitric oxide (NO) signaling. In blood vessels, endothelial nitric oxide synthase (eNOS) synthesizes NO to maintain vessel homeostasis. The biological actions of NO are compromised by superoxide that is generated by NADPH oxidases (NOXs). Herein we investigated how altered metabolism affects superoxide/NO balance in obesity. We found that eNOS expression and NO bioavailability are significantly decreased in endothelial cells (ECs) from T2D patients and animal models of obesity. In parallel, PFKFB3, a key glycolytic regulatory enzyme, is significantly increased in ECs of obese animals. EC overexpression of wild-type and a cytosol-restricted mutant PFKFB3 decreased NO production due to increased eNOS-T495 phosphorylation. PFKFB3 also blunted Akt-S473 phosphorylation, reducing stimulus-dependent phosphorylation of S1177 and the activation of eNOS. Furthermore, PFKFB3 enhanced the activities of NOX1 and NOX5, which are major contributors to endothelial dysfunction. Prolonged exposure of ECs to high glucose or TNFα, which are hallmarks of T2D, leads to increased PFKFB3 expression. These results demonstrate a novel functional relationship between endothelial metabolism, ROS, and NO balance that may contribute to endothelial dysfunction in obesity.
Bátori et al. (Fri,) conducted a other in Obesity and type 2 diabetes. PFKFB3 overexpression was evaluated on eNOS expression, NO bioavailability, and superoxide/NO balance. Increased PFKFB3 expression in endothelial cells from obese models decreases NO production and enhances NOX1/NOX5 activities, linking altered metabolism to endothelial dysfunction.