(556.8) Galectin-3 Regulates Oxidant Stress in Obesity

Poster Board Number: E100

Caleb Padgett (Medical College of Georgia at Augusta University), Andrew Speese (Medical College of Georgia at Augusta University), Cody Rosewater (Medical College of Georgia at Augusta University), Zachary Corley (Medical College of Georgia at Augusta University), James Mintz (Medical College of Georgia at Augusta University), David Fulton (Medical College of Georgia at Augusta University), David Stepp (Medical College of Georgia at Augusta University)

Objective: Investigate the mechanism by which overexpression of Galectin-3 (GAL3) in the endothelium of obese mice contributes to excess reactive oxygen species (ROS) production and subsequent vascular dysfunction.

Methods: db/db mice, a well-characterized model of human obesity, were crossed with mice lacking GAL3, a receptor for advanced glycation end products, to generate lean and obese mice with and without GAL3 deletion. Metabolic and cardiovascular endpoints were assessed by mRNA and protein expression in freshly isolated microvascular endothelial cells, microvascular reactivity assessed by pressure myography, and ROS production assessed by dihydroethidium (DHE) staining. Other previously characterized db/db colonies were utilized to further elucidate the mechanistic contributions of GAL3, including mice harboring deletions of NADPH Oxidase I (NOX1), Myostatin (MSTN), and Protein Tyrosine Phosphatase 1B (PTP1B).

Results: Deletion of GAL3 in obese mice had no observable effect on anatomical, metabolic, or plasma phenotype, except for normalizing levels of plasma ROS as evidenced by decrease in thiobarbituric acid reactive substances (TBARS). Obese mice exhibited profound endothelial dysfunction, which was rescued by deletion of GAL3. Our data demonstrate that NOX1, the predominant source of endothelial superoxide production, is significantly downregulated by GAL3 deletion, thereby restoring endothelial function and ameliorating endothelial ROS production in obesity. Furthermore, we demonstrate that GAL3-mediated NOX1 overexpression is amenable to improvements in metabolic status, such as lowering blood glucose with metformin, improving glucose handling by augmenting muscle mass through deletion of MSTN, or improving insulin signaling through deletion of PTP1B.

Conclusion: Taken 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 subsequent cardiovascular disease. This pathway presents an attractive target for therapeutic intervention to break the link between aberrant metabolism in obesity and its corresponding vascular pathologies.

C.A. Padgett is supported by National Institutes of Health (NIH) 1F31HL154646. D.W. Stepp and D.J. Fulton are supported by NIH 1R01HL147159.