Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis

Abstract Despite the associations between diabetic complications and vascular endothelial dysfunction, a direct therapeutic method targeting endothelial dysfunction remains poorly characterized. We have previously shown that chemical inhibition of G-protein-coupled receptor kinase 2 (GRK2) slightly...

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Autores principales:	Kumiko Taguchi, Mari Hida, Mami Hasegawa, Haruka Narimatsu, Takayuki Matsumoto, Tsuneo Kobayashi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6089618781004106a9ed062aad57b2e5
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spelling	oai:doaj.org-article:6089618781004106a9ed062aad57b2e52021-12-02T12:31:50ZSuppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis10.1038/s41598-017-08998-52045-2322https://doaj.org/article/6089618781004106a9ed062aad57b2e52017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08998-5https://doaj.org/toc/2045-2322Abstract Despite the associations between diabetic complications and vascular endothelial dysfunction, a direct therapeutic method targeting endothelial dysfunction remains poorly characterized. We have previously shown that chemical inhibition of G-protein-coupled receptor kinase 2 (GRK2) slightly enhances insulin sensitivity and reduces endothelial dysfunction in type 2 diabetic mice. In this study, we identified GRK2 as a novel therapeutic target of diabetic endothelial dysfunction and investigated the effect on diabetic endothelial dysfunction through the systemic administration of GRK2 siRNA using a hydrodynamic-based procedure, resulting in suppression of increased GRK2 protein levels in the liver. Suppressed GRK2 levels in the liver markedly improved glucose homeostasis, as well as improved the impaired endothelial Akt/eNOS-dependent signal activation (insulin-stimulated phosphorylation of Akt and eNOS) and vascular responses (clonidine-induced and insulin-induced endothelial-dependent relaxation response and phenylephrine-induced contractile response) in type 2 diabetic aortas. Interestingly, insulin-stimulated Akt/eNOS signaling was increased only by normalizing the glucose concentration in human umbilical vein endothelial cells (HUVECs) with GRK2 overexpression, suggesting of an important role of hepatic GRK2. Our results clarified the relationship among hepatic GRK2, glucose homeostasis, and vascular endothelial function. Liver-targeting GRK2 siRNA delivery represents a novel therapeutic tool to restore glucose homeostasis and reduce endothelial dysfunction.Kumiko TaguchiMari HidaMami HasegawaHaruka NarimatsuTakayuki MatsumotoTsuneo KobayashiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kumiko Taguchi Mari Hida Mami Hasegawa Haruka Narimatsu Takayuki Matsumoto Tsuneo Kobayashi Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis
description	Abstract Despite the associations between diabetic complications and vascular endothelial dysfunction, a direct therapeutic method targeting endothelial dysfunction remains poorly characterized. We have previously shown that chemical inhibition of G-protein-coupled receptor kinase 2 (GRK2) slightly enhances insulin sensitivity and reduces endothelial dysfunction in type 2 diabetic mice. In this study, we identified GRK2 as a novel therapeutic target of diabetic endothelial dysfunction and investigated the effect on diabetic endothelial dysfunction through the systemic administration of GRK2 siRNA using a hydrodynamic-based procedure, resulting in suppression of increased GRK2 protein levels in the liver. Suppressed GRK2 levels in the liver markedly improved glucose homeostasis, as well as improved the impaired endothelial Akt/eNOS-dependent signal activation (insulin-stimulated phosphorylation of Akt and eNOS) and vascular responses (clonidine-induced and insulin-induced endothelial-dependent relaxation response and phenylephrine-induced contractile response) in type 2 diabetic aortas. Interestingly, insulin-stimulated Akt/eNOS signaling was increased only by normalizing the glucose concentration in human umbilical vein endothelial cells (HUVECs) with GRK2 overexpression, suggesting of an important role of hepatic GRK2. Our results clarified the relationship among hepatic GRK2, glucose homeostasis, and vascular endothelial function. Liver-targeting GRK2 siRNA delivery represents a novel therapeutic tool to restore glucose homeostasis and reduce endothelial dysfunction.
format	article
author	Kumiko Taguchi Mari Hida Mami Hasegawa Haruka Narimatsu Takayuki Matsumoto Tsuneo Kobayashi
author_facet	Kumiko Taguchi Mari Hida Mami Hasegawa Haruka Narimatsu Takayuki Matsumoto Tsuneo Kobayashi
author_sort	Kumiko Taguchi
title	Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis
title_short	Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis
title_full	Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis
title_fullStr	Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis
title_full_unstemmed	Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis
title_sort	suppression of grk2 expression reduces endothelial dysfunction by restoring glucose homeostasis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6089618781004106a9ed062aad57b2e5
work_keys_str_mv	AT kumikotaguchi suppressionofgrk2expressionreducesendothelialdysfunctionbyrestoringglucosehomeostasis AT marihida suppressionofgrk2expressionreducesendothelialdysfunctionbyrestoringglucosehomeostasis AT mamihasegawa suppressionofgrk2expressionreducesendothelialdysfunctionbyrestoringglucosehomeostasis AT harukanarimatsu suppressionofgrk2expressionreducesendothelialdysfunctionbyrestoringglucosehomeostasis AT takayukimatsumoto suppressionofgrk2expressionreducesendothelialdysfunctionbyrestoringglucosehomeostasis AT tsuneokobayashi suppressionofgrk2expressionreducesendothelialdysfunctionbyrestoringglucosehomeostasis
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Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis

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