β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia

Journal of the American Heart Association
Keyvan Karimi GalougahiGemma A Figtree

Abstract

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. 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-glutat...Continue Reading

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Citations

Oct 21, 2016·Expert Opinion on Pharmacotherapy·Vojtech Hainer
Feb 2, 2018·Nature Reviews. Cardiology·Charlotte FarahJean-Luc Balligand
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May 11, 2021·Frontiers in Pharmacology·Kristen J BubbGemma A Figtree

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Methods Mentioned

BETA
coronary artery bypass
biopsy
electron paramagnetic resonance
co‐immunoprecipitation

Software Mentioned

Powerlab
Multi Gauge

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