Journal Article

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

Czesnikiewicz-Guzik, Marta, Moslehi, Javid, Saju, Blessy, Laksa, Iwona, Guzik, Tomasz J, Tomaszewski, Maciej, Dikalov, Sergey, Krolczyk, Jaroslaw, Jozefczuk, Ewelina, Hodorowicz-Zaniewska, Diana, Dziewulska, Anna, Mikolajczyk, Tomasz P, Siedlinski, Mateusz, Gara, Katarzyna, Dobrzyn, Agnieszka, Grodzicki, Tomasz, Dikalova, Anna, Nosalski, Ryszard, Dobosz, Aneta M, Harrison, David G, Streb, Joanna, Basta, Pawel, Chen, Wei, Szczepaniak, Piotr, Crea, Filippo, Sulicka-Grodzicka, Joanna, Maffia, Pasquale, Dormer, John

2022

Overview

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 from women with no history of such treatment matched for key clinical parameters. We explored mechanisms in WT and Nox4-/- mice and in human microvascular endothelial cells. Endothelium-dependent, NO-mediated vasodilatation was severely impaired in patients after NACT, while endothelium-independent responses remained normal. This was mimicked by a 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 Rho-associated protein kinase-dependent (ROCK-dependent) manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of the NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. A 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, and these were prevented in Nox4-/- mice and by pharmacological inhibition of Nox4 or Rock. Commonly used chemotherapeutic agents and, in particular, docetaxel alter vascular function by promoting the inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases.

• Publisher: American Society for Clinical Investigation
• Subject: Arteries / Biomedical research / Breast cancer / Cancer therapies / Cardiovascular disease / Cardiovascular diseases / Chemotherapy / CYBB protein / Cyclophosphamide / DNA methylation / Doxorubicin / Endothelial cells / Endothelium / Experiments / Hydrogen peroxide / Hypertension / Hypotheses / Kinases / Microvasculature / Morbidity / Mortality / NAD(P)H oxidase / Nitric oxide / NOX4 protein / Phosphorylation / Post-menopause / Protein kinase / Proteins / Radiation / Smooth muscle / Surgery / Therapeutic targets / Threonine / Vasodilation / Veins & arteries / Womens health