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)
![[img]](https://eprints.gla.ac.uk/style/images/fileicons/text.png) |
Text
272076.pdf - Published Version Available under License Creative Commons Attribution. 2MB |
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, Dr 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 |
| Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
| 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 |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information