β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia
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BACKGROUND: Perturbed balance between NO and O2 (•-). (ie, NO/redox imbalance) is central in the pathobiology of diabetes-induced vascular dysfunction. We examined whether stimulation of β3 adrenergic receptors (β3 ARs), coupled to endothelial nitric oxide synthase (eNOS) activation, would re-establish NO/redox balance, relieve oxidative inhibition of the membrane proteins eNOS and Na(+)-K(+) (NK) pump, and improve vascular function in a new animal model of hyperglycemia.
METHODS AND RESULTS: We established hyperglycemia in male White New Zealand rabbits by infusion of S961, a competitive high-affinity peptide inhibitor of the insulin receptor. Hyperglycemia impaired endothelium-dependent vasorelaxation by "uncoupling" of eNOS via glutathionylation (eNOS-GSS) that was dependent on NADPH oxidase activity. Accordingly, NO levels were lower while O2 (•-) levels were higher in hyperglycemic rabbits. Infusion of the β3 AR agonist CL316243 (CL) decreased eNOS-GSS, reduced O2 (•-), restored NO levels, and improved endothelium-dependent relaxation. CL decreased hyperglycemia-induced NADPH oxidase activation as suggested by co-immunoprecipitation experiments, and it increased eNOS co-immunoprecipitation with glutaredoxin-1, which may reflect promotion of eNOS de-glutathionylation by CL. Moreover, CL reversed hyperglycemia-induced glutathionylation of the β1 NK pump subunit that causes NK pump inhibition, and improved K(+)-induced vasorelaxation that reflects enhancement in NK pump activity. Lastly, eNOS-GSS was higher in vessels of diabetic patients and was reduced by CL, suggesting potential significance of the experimental findings in human diabetes.
CONCLUSIONS: β3 AR activation restored NO/redox balance and improved endothelial function in hyperglycemia. β3 AR agonists may confer protection against diabetes-induced vascular dysfunction.
|Journal||American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease|
|Publication status||Published - 19 Feb 2016|
- Adrenergic beta-3 Receptor Agonists, Animals, Blood Glucose, Diabetes Mellitus, Experimental, Diabetic Angiopathies, Dioxoles, Dose-Response Relationship, Drug, Endothelium, Vascular, Enzyme Activation, Glutathione, Hyperglycemia, Hypoglycemic Agents, Male, NADPH Oxidase, Nitric Oxide, Nitric Oxide Synthase Type III, Oxidation-Reduction, Oxidative Stress, Peptides, Rabbits, Receptors, Adrenergic, beta-3, Signal Transduction, Sodium-Potassium-Exchanging ATPase, Superoxides, Time Factors, Journal Article, Research Support, Non-U.S. Gov't