Inhibitor of G protein-coupled receptor kinase 2 normalizes vascular endothelial function in type 2 diabetic mice by improving β-arrestin 2 translocation and ameliorating Akt/eNOS signal dysfunction

Endocrinology
Kumiko TaguchiTsuneo Kobayashi

Abstract

In type 2 diabetes, although Akt/endothelial NO synthase (eNOS) activation is known to be negatively regulated by G protein-coupled receptor kinase 2 (GRK2), it is unclear whether the GRK2 inhibitor would have therapeutic effects. Here we examined the hypotensive effect of the GRK2 inhibitor and its efficacy agonist both vascular (aortic) endothelial dysfunction (focusing especially on the Akt/eNOS pathway) and glucose intolerance in two type 2 diabetic models (ob/ob mice and nicotinamide+streptozotocin-induced diabetic mice). Mice were treated with a single injection of the GRK2 inhibitor or vehicle, and the therapeutic effects were compared by examining vascular function and by Western blotting. The GRK2 inhibitor lowered blood pressure in both diabetic models but not in their age-matched controls. The GRK2 inhibitor significantly improved clonidine-induced relaxation only in diabetic (ob/ob and DM) mice, with accompanying attenuations of GRK2 activity and translocation to the plasma membrane. These protective effects of the GRK2 inhibitor may be attributable to the augmented Akt/eNOS pathway activation (as evidenced by increases in Akt phosphorylation at Ser(473) and at Thr(308), and eNOS phosphorylation at Ser(1177)) and to...Continue Reading

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Citations

Mar 28, 2013·High Blood Pressure & Cardiovascular Prevention : the Official Journal of the Italian Society of Hypertension·Gaetano SantulliGuido Iaccarino
Dec 9, 2015·Archives of Physiology and Biochemistry·Elisa LucasRocio Vila-Bedmar
Oct 9, 2015·Journal of Smooth Muscle Research = Nihon Heikatsukin Gakkai Kikanshi·Kumiko TaguchiTsuneo Kobayashi
Dec 3, 2015·Molecular Nutrition & Food Research·Kumiko TaguchiTsuneo Kobayashi
May 21, 2017·American Journal of Physiology. Heart and Circulatory Physiology·Daniela Dal-SeccoJamil Assreuy
Aug 4, 2015·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Kumiko Taguchi
Feb 22, 2018·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Kumiko TaguchiTsuneo Kobayashi
Aug 18, 2017·Scientific Reports·Kumiko TaguchiTsuneo Kobayashi
Jun 28, 2018·Naunyn-Schmiedeberg's Archives of Pharmacology·Kumiko TaguchiTsuneo Kobayashi
Aug 21, 2020·BMJ Open Diabetes Research & Care·Kentaro UshijimaAkio Fujimura
Aug 1, 2018·Scientific Reports·Elena Tutunea-FatanStephen S G Ferguson

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