2022 · Cardiovascular Research · Oxford University Press · added 2026-04-21
AbstractFunding AcknowledgementsType of funding sources: Public grant(s) – Nat Show more
AbstractFunding AcknowledgementsType of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health (NIH)IntroductionThe prevalence of obesity continues to rise to unprecedented levels, and with it, a corresponding increase in the incidence of cardiovascular disease (CVD). While obesity is indeed accepted as one of the most prominent risk factors for CVD, the precise molecular mechanisms by which aberrant metabolism is linked to cardiovascular function remain incompletely understood. One prevailing hypothesis is that overproduction of reactive oxygen species (ROS) from increased metabolism significantly contributes to endothelial dysfunction, which precedes many cardiovascular events such as atherosclerosis and stroke.PurposeIn this study, we hypothesized that a receptor for advanced glycation end products, Galectin-3 (GAL3), acts as a metabolic sensor and regulates endothelial ROS production in obesity.MethodsObese db/db mice were crossed with mice lacking GAL3, and endothelial gene expression, microvascular reactivity, and ROS production were assessed.ResultsWe demonstrate that NADPH Oxidase I (NOX1), the predominant source of endothelial superoxide production, is down-regulated by GAL3 deletion, thereby rescuing endothelial function and ameliorating endothelial ROS production in obesity. Furthermore, we demonstrate that GAL3-mediated NOX1 over-expression is amenable to improvements in metabolic status, such as lowering blood glucose with metformin, improving glucose handling by augmenting muscle mass, or improving insulin signaling through deletion of Protein Tyrosine Phosphatase 1B (PTP1B).ConclusionTaken together, these data demonstrate that the overproduction of superoxide by endothelial NOX1 is regulated by the metabolic sensor GAL3 in obesity, leading to endothelial dysfunction and CVD. This pathway presents an attractive target for therapeutic intervention to break the link between aberrant metabolism in obesity and its corresponding vascular pathologies.Show less