1. Differential effects of cyclo-oxygenase 1 and 2 inhibition on angiogenesis inhibitor-induced hypertension and kidney damage.
- Author
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Mirabito Colafella KM, van Dorst DCH, Neuman RI, Doorn LV, Neves KB, Montezano AC, Garrelds IM, van Veghel R, de Vries R, Uijl E, Clahsen-van Groningen MC, Baelde HJ, van den Meiracker AH, Touyz RM, Visser W, Danser AHJ, and Versmissen J
- Subjects
- Angiogenesis Inhibitors therapeutic use, Animals, Aspirin pharmacology, Cyclooxygenase 1 metabolism, Cyclooxygenase 2 metabolism, Endothelin-1 metabolism, Epoprostenol metabolism, Epoprostenol pharmacology, Epoprostenol therapeutic use, Female, Humans, Kidney metabolism, Pregnancy, Prostaglandin-Endoperoxide Synthases metabolism, Rats, Vascular Endothelial Growth Factor A metabolism, Hypertension chemically induced, Hypertension drug therapy, Hypertension metabolism, Pre-Eclampsia chemically induced, Pre-Eclampsia drug therapy, Pre-Eclampsia metabolism
- Abstract
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- or high-dose aspirin for 8 days (n=5-7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- 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- 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., (© 2022 The Author(s).)
- Published
- 2022
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