Breast cancer chemotherapy induces vascular dysfunction and hypertension through NOX4 dependent mechanism

Szczepaniak, P. et al. (2022) Breast cancer chemotherapy induces vascular dysfunction and hypertension through NOX4 dependent mechanism. Journal of Clinical Investigation, 132(13), e149117. (doi: 10.1172/JCI149117) (PMID:35617030) (PMCID:PMC9246378)

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Abstract

Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets. We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin and cyclophosphamide (NACT), and women with no history of such treatment matched for key clinical parameters. Mechanisms were explored in wild-type and Nox4-/- mice and human microvascular endothelial cells. Endothelium-dependent vasodilatation is severely impaired in patients after NACT, while endothelium-independent responses remain normal. This was mimicked by 24-hour exposure of arteries to NACT agents ex-vivo. When applied individually, only docetaxel impaired endothelial function in human vessels. Mechanistic studies showed that NACT increased inhibitory eNOS phosphorylation of threonine 495 in a ROCK-dependent manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. NOX4 increase in human arteries may be mediated epigenetically by diminished DNA methylation of the NOX4 promoter. Docetaxel induced endothelial dysfunction and hypertension in mice. These were prevented in Nox4-/- and by pharmacological inhibition of Nox4 or Rock. Commonly used chemotherapeutic agents, and in particular, docetaxel, alter vascular function by promoting inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nosalski, Mr Ryszard and Maffia, Professor Pasquale and Mikolajczyk, Dr Tomasz and Szczepaniak, Mr Piotr and Guzik, Professor Tomasz and Czesnikiewicz-Guzik, Dr Marta and Siedlinski, Mr Mateusz and Saju, Blessy and Harrison, Professor David
Authors: Szczepaniak, P., Siedlinski, M., Hodorowicz-Zaniewska, D., Nosalski, R., Mikolajczyk, T. P., Dobosz, A. M., Dikalova, A., Dikalov, S., Streb, J., Gara, K., Basta, P., Krolczyk, J., Sulicka-Grodzicka, J., Jozefczuk, E., Dziewulska, A., Saju, B., Laksa, I., Chen, W., Dormer, J., Tomaszewski, M., Maffia, P., Czesnikiewicz-Guzik, M., Crea, F., Dobrzyn, A., Moslehi, J., Grodzicki, T., Harrison, D. G., and Guzik, T. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School
Journal Name:Journal of Clinical Investigation
Publisher:Americal Society for Clinical Investigation
ISSN:0021-9738
ISSN (Online):1558-8238
Published Online:26 May 2022
Copyright Holders:Copyright © 2022 Szczepaniak et al.
First Published:First published in Journal of Clinical Investigation 132(13): e149117
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
300798A study of the roles of the immune and inflammatory systems in hypertensionTomasz GuzikEuropean Research Council (ERC)726318CAMS - Cardiovascular Science
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