β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia
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β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia. / Karimi Galougahi, Keyvan; Liu, Chia-Chi; Garcia, Alvaro; Gentile, Carmine; Fry, Natasha A; Hamilton, Elisha J; Hawkins, Clare L; Figtree, Gemma A.
In: American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease, Vol. 5, No. 2, e002824, 19.02.2016.Research output: Contribution to journal › Journal article › Research › peer-review
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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 - 2016/2/19
Y1 - 2016/2/19
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
VL - 5
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 2
M1 - e002824
ER -
ID: 174496899