Differential effects of cyclo-oxygenase 1 and 2 inhibition on angiogenesis inhibitor-induced hypertension and kidney damage

Mirabito Colafella, K. M. et al. (2022) Differential effects of cyclo-oxygenase 1 and 2 inhibition on angiogenesis inhibitor-induced hypertension and kidney damage. Clinical Science, 136(9), pp. 675-694. (doi: 10.1042/CS20220182) (PMID:35441670) (PMCID:PMC9093150)

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Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a “preeclampsia-like” syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low-dose or high-dose aspirin for 8 days (n=5-7/group). Our results demonstrate that prostacyclin (PGI2) and ET-1 are increased during angiogenesis inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low-dose and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low-dose and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Montezano, Dr Augusto and Touyz, Professor Rhian and Neves, Dr Karla
Authors: Mirabito Colafella, K. M., Dorst, D. C.H. v., Neuman, R., Doorn, L. v., Neves, K. B., Montezano, A. C., Garrelds, I. M., van Veghel, R., de Vries, R., Uijl, E., Clahsen-van Groningen, M. C., Baelde, H., van den Meiracker, A. H., Touyz, R. M., Visser, W., Danser, A.H. J., and Versmissen, J.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Clinical Science
Publisher:Portland Press
ISSN (Online):1470-8736
Published Online:20 April 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Clinical Science 136(9): 675-694
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303944BHF Centre of ExcellenceColin BerryBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science
300689Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762CAMS - Cardiovascular Science