Doxorubicin Impairs Smooth Muscle Cell Contraction: Novel Insights in Vascular Toxicity

Clinical and animal studies have demonstrated that chemotherapeutic doxorubicin (DOX) increases arterial stiffness, a predictor of cardiovascular risk. Despite consensus about DOX-impaired endothelium-dependent vasodilation as a contributing mechanism, some studies have reported conflicting results...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 22; no. 23; p. 12812
Main Authors:	Bosman, Matthias, Krüger, Dustin N, Favere, Kasper, Wesley, Callan D, Neutel, Cédric H G, Van Asbroeck, Birgit, Diebels, Owen R, Faes, Bart, Schenk, Timen J, Martinet, Wim, De Meyer, Guido R Y, Van Craenenbroeck, Emeline M, Guns, Pieter-Jan D F
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 26-11-2021 MDPI
Subjects:	Angiotensin Angiotensin II Animals Antibiotics, Antineoplastic - toxicity Aorta arterial stiffness Biocompatibility Blood pressure Calcium (reticular) Calcium - metabolism Calcium channels Calcium channels (voltage-gated) Calcium Channels - metabolism Calcium influx Calcium ions cardio-oncology Cardiovascular diseases Channels Coronary vessels Diltiazem Doxorubicin Doxorubicin - toxicity Drug dosages endothelial dysfunction Endothelin 1 Endothelins Endothelium Endothelium, Vascular - drug effects Endothelium, Vascular - pathology Experiments Male Mice Mice, Inbred C57BL Muscle Contraction Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - pathology Muscles Nitric oxide non-selective cation channel Phenylephrine Sarcoplasmic reticulum Serotonin Smooth muscle Stiffness Toxicity Transient receptor potential proteins vascular smooth muscle cell contraction Vascular Stiffness - drug effects Vasoconstriction Vasodilation arterial stiffness vascular smooth muscle cell contraction cardio-oncology doxorubicin non-selective cation channel endothelial dysfunction
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Summary:	Clinical and animal studies have demonstrated that chemotherapeutic doxorubicin (DOX) increases arterial stiffness, a predictor of cardiovascular risk. Despite consensus about DOX-impaired endothelium-dependent vasodilation as a contributing mechanism, some studies have reported conflicting results on vascular smooth muscle cell (VSMC) function after DOX treatment. The present study aimed to investigate the effects of DOX on VSMC function. To this end, mice received a single injection of 4 mg DOX/kg, or mouse aortic segments were treated ex vivo with 1 μM DOX, followed by vascular reactivity evaluation 16 h later. Phenylephrine (PE)-induced VSMC contraction was decreased after DOX treatment. DOX did not affect the transient PE contraction dependent on Ca release from the sarcoplasmic reticulum (0 mM Ca ), but it reduced the subsequent tonic phase characterised by Ca influx. These findings were supported by similar angiotensin II and attenuated endothelin-1 contractions. The involvement of voltage-gated Ca channels in DOX-decreased contraction was excluded by using levcromakalim and diltiazem in PE-induced contraction and corroborated by similar K and serotonin contractions. Despite the evaluation of multiple blockers of transient receptor potential channels, the exact mechanism for DOX-decreased VSMC contraction remains elusive. Surprisingly, DOX reduced ex vivo but not in vivo arterial stiffness, highlighting the importance of appropriate timing for evaluating arterial stiffness in DOX-treated patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms222312812