Doxorubicin increases G-protein coupled receptor-mediated vasoconstriction in coronary arteries via the mitogen-activated protein kinase kinase 1/2 pathway

Caroline Lozahic; H Maddock; Mark Wheatley; Hardip Sandhu

doi:10.1016/j.ejphar.2025.178162

Doxorubicin increases G-protein coupled receptor-mediated vasoconstriction in coronary arteries via the mitogen-activated protein kinase kinase 1/2 pathway

Caroline Lozahic
, H Maddock
, Mark Wheatley
, Hardip Sandhu

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Anthracyclines are one of the most effective chemotherapy drugs, but are associated with cardiotoxicity, including hypertension, however, little is known about the effect of anthracyclines on the vascular tone. Emerging data indicate that the anthracycline doxorubicin induces increases in vascular tone via endothelin subtype A (ETA) and B (ETB), serotonin (5-HT) subtype 1B (5-HT1B), and thromboxane prostanoid (TP) G-protein coupled receptors (GPCRs) in coronary arteries. This study examined for the first time whether the mitogen-activated protein kinase kinase 1/2 (MEK 1/2) pathway is involved in the doxorubicin-induced increase of vasoconstriction. This study used an organ culture model, where left anterior descending arteries (LAD) from rats were incubated with doxorubicin (0.5 µM) in the absence and presence of the MEK 1/2 specific inhibitor U0126 (5 µM), and GPCR-mediated vasoconstriction was analysed by wire-myography. GPCR mRNA levels and GPCR expression and localisation on LAD arteries were investigated by real-time PCR and immunohistochemistry. Doxorubicin treatment increased the vasoconstriction through ETA (278% increase at 10-8.5 M endothelin-1 (ET-1), 5-HT1B (193% increase at 10-5.5 M 5-carboxamidotryptamine (5-CT)) and TP (32% increase at 10-6.5 M U46619) receptors, and decreased ETB-mediated vasoconstriction (37% decrease at 10-7.5 M Sarafotoxin 6c (S6c)), however, a decrease in ETB mRNA was detected. Co-incubation with U0126 decreased doxorubicin-mediated increased vasoconstriction through ETA, 5-HT1B, and TP receptors. This novel study shows that doxorubicin treatment of LAD arteries increases vasoconstriction through ETA, 5-HT1B, and TP receptors through the MEK 1/2 pathway.

Original language	English
Article number	178162
Number of pages	9
Journal	European Journal of Pharmacology
Volume	1006
Early online date	15 Sept 2025
DOIs	https://doi.org/10.1016/j.ejphar.2025.178162
Publication status	Published - 5 Nov 2025

Bibliographical note

© 2025 Elsevier

Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

This document is the author’s Accepted Manuscript, incorporating any revisions agreed during the peer-review process. Some differences between the published version and this version may remain and you are advised to consult the published version if you wish to cite from it.

Funding

This research was supported by the Research Centre for Health & Life Sciences (Research Institute for Health & Wellbeing) at Coventry University, United Kingdom. The support from DTA3/COFUND Marie Skłodowska-Curie PhD Fellowship programme (partly funded by the Horizon 2020 European Programme) was greatly appreciated. The assistance and support from senior technician Mr Mark Bodycote and InoCardia Ltd. staff members Dr Adam Linekar and Dr Josh Hurst are greatly appreciated.

Funders
Durham University
Coventry University
H2020 Marie Skłodowska-Curie Actions
UK Doctoral Training Alliance (DTA)
Horizon Europe

Keywords

Doxorubicin
vasotoxicity
G-protein coupled receptors
vascular tone
hypertension
MEK 1/2 pathway

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10.1016/j.ejphar.2025.178162

Cite this

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title = "Doxorubicin increases G-protein coupled receptor-mediated vasoconstriction in coronary arteries via the mitogen-activated protein kinase kinase 1/2 pathway",

abstract = "Anthracyclines are one of the most effective chemotherapy drugs, but are associated with cardiotoxicity, including hypertension, however, little is known about the effect of anthracyclines on the vascular tone. Emerging data indicate that the anthracycline doxorubicin induces increases in vascular tone via endothelin subtype A (ETA) and B (ETB), serotonin (5-HT) subtype 1B (5-HT1B), and thromboxane prostanoid (TP) G-protein coupled receptors (GPCRs) in coronary arteries. This study examined for the first time whether the mitogen-activated protein kinase kinase 1/2 (MEK 1/2) pathway is involved in the doxorubicin-induced increase of vasoconstriction. This study used an organ culture model, where left anterior descending arteries (LAD) from rats were incubated with doxorubicin (0.5 µM) in the absence and presence of the MEK 1/2 specific inhibitor U0126 (5 µM), and GPCR-mediated vasoconstriction was analysed by wire-myography. GPCR mRNA levels and GPCR expression and localisation on LAD arteries were investigated by real-time PCR and immunohistochemistry. Doxorubicin treatment increased the vasoconstriction through ETA (278\% increase at 10-8.5 M endothelin-1 (ET-1), 5-HT1B (193\% increase at 10-5.5 M 5-carboxamidotryptamine (5-CT)) and TP (32\% increase at 10-6.5 M U46619) receptors, and decreased ETB-mediated vasoconstriction (37\% decrease at 10-7.5 M Sarafotoxin 6c (S6c)), however, a decrease in ETB mRNA was detected. Co-incubation with U0126 decreased doxorubicin-mediated increased vasoconstriction through ETA, 5-HT1B, and TP receptors. This novel study shows that doxorubicin treatment of LAD arteries increases vasoconstriction through ETA, 5-HT1B, and TP receptors through the MEK 1/2 pathway.",

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AB - Anthracyclines are one of the most effective chemotherapy drugs, but are associated with cardiotoxicity, including hypertension, however, little is known about the effect of anthracyclines on the vascular tone. Emerging data indicate that the anthracycline doxorubicin induces increases in vascular tone via endothelin subtype A (ETA) and B (ETB), serotonin (5-HT) subtype 1B (5-HT1B), and thromboxane prostanoid (TP) G-protein coupled receptors (GPCRs) in coronary arteries. This study examined for the first time whether the mitogen-activated protein kinase kinase 1/2 (MEK 1/2) pathway is involved in the doxorubicin-induced increase of vasoconstriction. This study used an organ culture model, where left anterior descending arteries (LAD) from rats were incubated with doxorubicin (0.5 µM) in the absence and presence of the MEK 1/2 specific inhibitor U0126 (5 µM), and GPCR-mediated vasoconstriction was analysed by wire-myography. GPCR mRNA levels and GPCR expression and localisation on LAD arteries were investigated by real-time PCR and immunohistochemistry. Doxorubicin treatment increased the vasoconstriction through ETA (278% increase at 10-8.5 M endothelin-1 (ET-1), 5-HT1B (193% increase at 10-5.5 M 5-carboxamidotryptamine (5-CT)) and TP (32% increase at 10-6.5 M U46619) receptors, and decreased ETB-mediated vasoconstriction (37% decrease at 10-7.5 M Sarafotoxin 6c (S6c)), however, a decrease in ETB mRNA was detected. Co-incubation with U0126 decreased doxorubicin-mediated increased vasoconstriction through ETA, 5-HT1B, and TP receptors. This novel study shows that doxorubicin treatment of LAD arteries increases vasoconstriction through ETA, 5-HT1B, and TP receptors through the MEK 1/2 pathway.

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KW - vasotoxicity

KW - G-protein coupled receptors

KW - vascular tone

KW - hypertension

KW - MEK 1/2 pathway

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DO - 10.1016/j.ejphar.2025.178162

M3 - Article

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ER -

Doxorubicin increases G-protein coupled receptor-mediated vasoconstriction in coronary arteries via the mitogen-activated protein kinase kinase 1/2 pathway

Abstract

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