Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of clinical investigation, 2022-07, Vol.132 (13)

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2022

Quelle

EZB*

Beschreibungen/Notizen

• 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.