NADPH oxidase 5 is a pro‐contractile Nox isoform and a point of cross‐talk for calcium and redox signaling‐implications in vascular function

Montezano, A. C. et al. (2018) NADPH oxidase 5 is a pro‐contractile Nox isoform and a point of cross‐talk for calcium and redox signaling‐implications in vascular function. Journal of the American Heart Association, 7(12), e009388. (doi:10.1161/JAHA.118.009388) (PMID:29907654) (PMCID:PMC6220544)

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Abstract

Background: NADPH Oxidase 5 (Nox5) is a calcium‐sensitive superoxide‐generating Nox. It is present in lower forms and higher mammals, but not in rodents. Nox5 is expressed in vascular cells, but the functional significance remains elusive. Given that contraction is controlled by calcium and reactive oxygen species, both associated with Nox5, we questioned the role of Nox5 in pro‐contractile signaling and vascular function. Methods and Results: Transgenic mice expressing human Nox5 in a vascular smooth muscle cell–specific manner (Nox5 mice) and Rhodnius prolixus, an arthropod model that expresses Nox5 endogenoulsy, were studied. Reactive oxygen species generation was increased systemically and in the vasculature and heart in Nox5 mice. In Nox5‐expressing mice, agonist‐induced vasoconstriction was exaggerated and endothelium‐dependent vasorelaxation was impaired. Vascular structural and mechanical properties were not influenced by Nox5. Vascular contractile responses in Nox5 mice were normalized by N‐acetylcysteine and inhibitors of calcium channels, calmodulin, and endoplasmic reticulum ryanodine receptors, but not by GKT137831 (Nox1/4 inhibitor). At the cellular level, vascular changes in Nox5 mice were associated with increased vascular smooth muscle cell [Ca2+]i, increased reactive oxygen species and nitrotyrosine levels, and hyperphosphorylation of pro‐contractile signaling molecules MLC20 (myosin light chain 20) and MYPT1 (myosin phosphatase target subunit 1). Blood pressure was similar in wild‐type and Nox5 mice. Nox5 did not amplify angiotensin II effects. In R. prolixus, gastrointestinal smooth muscle contraction was blunted by Nox5 silencing, but not by VAS2870 (Nox1/2/4 inhibitor). Conclusions: Nox5 is a pro‐contractile Nox isoform important in redox‐sensitive contraction. This involves calcium‐calmodulin and endoplasmic reticulum–regulated mechanisms. Our findings define a novel function for vascular Nox5, linking calcium and reactive oxygen species to the pro‐contractile molecular machinery in vascular smooth muscle cells.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rios, Dr Francisco and Harvey, Dr Adam and Graham, Dr Delyth and Lopes, Dr Rheure and Persson, Dr Patrik and De Lucca Camargo, Dr Livia and Dulak-Lis, Ms Maria and Palacios, Mr Roberto and Montezano, Dr Augusto and Touyz, Professor Rhian and Neves, Dr Karla Bianca
Authors: Montezano, A. C., De Lucca Camargo, L., Persson, P., Rios, F. J., Harvey, A. P., Agnostopoulou, A., Palacios, R., Gandara, A. C. P., Alves-Lopes, R., Neves, K. B., Dulak-Lis, M., Holterman, C. E., Lagerblad de Oliveira, P., Graham, D., Kennedy, C., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American Heart Association
Publisher:American Heart Association
ISSN:2047-9980
ISSN (Online):2047-9980
Published Online:12 June 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Journal of the American Heart Association 7(12): e009388
Publisher Policy:Reproduced under a Creative Commons License

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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