Ca2+-dependent NOX5 (NADPH oxidase 5) exaggerates cardiac hypertrophy through reactive oxygen species production

Zhao, G.-J. et al. (2020) Ca2+-dependent NOX5 (NADPH oxidase 5) exaggerates cardiac hypertrophy through reactive oxygen species production. Hypertension, 76(3), pp. 827-838. (doi: 10.1161/HYPERTENSIONAHA.120.15558)

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NOX5 (NADPH oxidase 5) is a homolog of the gp91phox subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca2+-sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and β-MHC (β-myosin heavy chain) and prohypertrophic genes (Nppa, Nppb, and Myh7) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specific NOX5 trangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy in NOX5 trangenic. Our study defines Ca2+-regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction.

Item Type:Articles
Additional Information:This work was supported by grants from the National Natural Science Foundation of China (No. 81970011 to P.Z.) and Zhongnan Hospital of Wuhan University, Technology and Innovation Seed Found (znpy2018118).
Glasgow Author(s) Enlighten ID:Montezano, Dr Augusto and Touyz, Professor Rhian
Authors: Zhao, G.-J., Zhao, C.-L., Ouyang, S., Deng, K.-Q., Zhu, L.-H., Montezano, A. C., Zhang, C., Hu, F., Zhu, X.-Y., Tian, S., Liu, X., Ji, Y.-X., Zhang, P., Zhang, X.-J., She, Z.-G., Touyz, R. M., and Li, H.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Hypertension
Publisher:American Heart Association
ISSN (Online):1524-4563
Published Online:20 July 2020
Copyright Holders:Copyright © 2020 American Heart Association, Inc.
First Published:First published in Hypertension 76(3):827-838
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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