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 journalJournal articleResearchpeer-review

Harvard

Karimi Galougahi, K, Liu, C-C, Garcia, A, Gentile, C, Fry, NA, Hamilton, EJ, Hawkins, CL & Figtree, GA 2016, 'β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia', American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease, vol. 5, no. 2, e002824. https://doi.org/10.1161/JAHA.115.002824

APA

Karimi Galougahi, K., Liu, C-C., Garcia, A., Gentile, C., Fry, N. A., Hamilton, E. J., ... Figtree, G. A. (2016). β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia. American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease, 5(2), [e002824]. https://doi.org/10.1161/JAHA.115.002824

Vancouver

Karimi Galougahi K, Liu C-C, Garcia A, Gentile C, Fry NA, Hamilton EJ et al. β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia. American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease. 2016 Feb 19;5(2). e002824. https://doi.org/10.1161/JAHA.115.002824

Author

Karimi Galougahi, Keyvan ; Liu, Chia-Chi ; Garcia, Alvaro ; Gentile, Carmine ; Fry, Natasha A ; Hamilton, Elisha J ; Hawkins, Clare L ; Figtree, Gemma A. / β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia. In: American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease. 2016 ; Vol. 5, No. 2.

Bibtex

@article{439dee95e9b047e7b4b5e20f0cb9fc33,
title = "β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia",
abstract = "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.",
keywords = "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",
author = "{Karimi Galougahi}, Keyvan and Chia-Chi Liu and Alvaro Garcia and Carmine Gentile and Fry, {Natasha A} and Hamilton, {Elisha J} and Hawkins, {Clare L} and Figtree, {Gemma A}",
note = "{\circledC} 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.",
year = "2016",
month = "2",
day = "19",
doi = "10.1161/JAHA.115.002824",
language = "English",
volume = "5",
journal = "American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "2",

}

RIS

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 - American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease

JF - American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease

SN - 2047-9980

IS - 2

M1 - e002824

ER -

ID: 174496899