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

TY - JOUR

T1 - β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia

AU - Karimi Galougahi, Keyvan

AU - Liu, Chia-Chi

AU - Garcia, Alvaro

AU - Gentile, Carmine

AU - Fry, Natasha A

AU - Hamilton, Elisha J

AU - Hawkins, Clare L

AU - Figtree, Gemma A

N1 - © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

KW - Adrenergic beta-3 Receptor Agonists

KW - Animals

KW - Blood Glucose

KW - Diabetes Mellitus, Experimental

KW - Diabetic Angiopathies

KW - Dioxoles

KW - Dose-Response Relationship, Drug

KW - Endothelium, Vascular

KW - Enzyme Activation

KW - Glutathione

KW - Hyperglycemia

KW - Hypoglycemic Agents

KW - Male

KW - NADPH Oxidase

KW - Nitric Oxide

KW - Nitric Oxide Synthase Type III

KW - Oxidation-Reduction

KW - Oxidative Stress

KW - Peptides

KW - Rabbits

KW - Receptors, Adrenergic, beta-3

KW - Signal Transduction

KW - Sodium-Potassium-Exchanging ATPase

KW - Superoxides

KW - Time Factors

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1161/jaha.115.002824

DO - 10.1161/jaha.115.002824

M3 - Journal article

C2 - 26896479

SN - 2047-9980

VL - 5

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 2

M1 - e002824

ER -