Brown adipose tissue regulates small artery function through NADPH oxidase 4-derived hydrogen peroxide and redox-sensitive protein kinase G-1α

Friederich-Persson, M., Nguyen Dinh Cat, A., Persson, P., Montezano, A. C. and Touyz, R. M. (2017) Brown adipose tissue regulates small artery function through NADPH oxidase 4-derived hydrogen peroxide and redox-sensitive protein kinase G-1α. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(3), pp. 455-465. (doi:10.1161/atvbaha.116.308659) (PMID:28062507)

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Abstract

Objective—Biomedical interest in brown adipose tissue (BAT) has increased since the discovery of functionally active BAT in adult humans. Although white adipose tissue (WAT) influences vascular function, vascular effects of BAT are elusive. Thus, we investigated the regulatory role and putative vasoprotective effects of BAT, focusing on hydrogen peroxide, nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4), and redox-sensitive signaling. Approach and Results—Vascular reactivity was assessed in wild-type and Nox4-knockout mice (Nox4−/−) by wire myography in the absence and presence of perivascular adipose tissue of different phenotypes from various adipose depots: (1) mixed WAT/BAT (inguinal adipose tissue) and (2) WAT (epididymal visceral fat) and BAT (intrascapular fat). In wild-type mice, epididymal visceral fat and perivascular adipose tissue increased EC50 to noradrenaline without affecting maximum contraction. BAT increased EC50 and significantly decreased maximum contraction, which were prevented by a hydrogen peroxide scavenger (polyethylene glycated catalase) and a specific cyclic GMP–dependent protein kinase G type-1α inhibitor (DT-3), but not by inhibition of endothelial nitric oxide synthase or guanylate cyclase. BAT induced dimerization of cyclic GMP–dependent protein kinase G type-1α and reduced phosphorylation of myosin light chain phosphatase subunit 1 and myosin light chain 20. BAT from Nox4-knockout mice displayed reduced hydrogen peroxide levels and no anticontractile effects. Perivascular adipose tissue from β3 agonist–treated mice displayed browned perivascular adipose tissue and an increased anticontractile effect. Conclusions—We identify a novel vasoprotective action of BAT through an anticontractile effect that is mechanistically different to WAT. Specifically, BAT, via Nox4-derived hydrogen peroxide, induces cyclic GMP–dependent protein kinase G type-1α activation, resulting in reduced vascular contractility. BAT may constitute an interesting therapeutic target to restore vascular function and prevent vascular complications in cardiovascular diseases.

Item Type:Articles
Additional Information:R Touyz was also supported through a BHF Chair (CH/12/429762)
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Friederich-Persson, Dr Malou and Montezano, Dr Augusto and Nguyen Dinh Cat, Dr Aurelie and Persson, Dr Patrik and Touyz, Professor Rhian
Authors: Friederich-Persson, M., Nguyen Dinh Cat, A., Persson, P., Montezano, A. C., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher:American Heart Association
ISSN:1079-5642
ISSN (Online):1524-4636
Published Online:22 December 2016
Copyright Holders:Copyright © 2017 American Heart Association, Inc.
First Published:First published in Arteriosclerosis, Thrombosis, and Vascular Biology 37(3):455-465
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607382Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)RG/13/7/30099RI CARDIOVASCULAR & MEDICAL SCIENCES
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES