BCR-ABL tyrosine kinase inhibitors promote pathological changes in dilator phenotype in the human microvasculature. Microcirculation 2020 Oct;27(7):e12625
Date
05/13/2020Pubmed ID
32395853Pubmed Central ID
PMC7606774DOI
10.1111/micc.12625Scopus ID
2-s2.0-85090145617 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
OBJECTIVE: Treatment with BCR-ABL tyrosine kinase inhibitors (TKIs) is the standard of care for patients with chronic myeloid leukemia, however evidence indicates these compounds may have cardiovascular side-effects. This study sought to determine if ex vivo exposure of human adipose arterioles to the BCR-ABL TKIs imatinib and nilotinib causes endothelial dysfunction.
METHODS: Human adipose arterioles were incubated overnight in cell culture media containing vehicle (PBS), imatinib (10 µmol/L) or nilotinib (100 µmol/L). Arterioles were cannulated onto glass pipettes and flow mediated dilation (FMD) was assessed via video microscopy. To determine the mechanism of vasodilation, FMD was re-assessed in the presence of either the nitric oxide synthase inhibitor L-NAME (100 µmol/L) or the H2 O2 scavenger PEG-Catalase (500 U/mL).
RESULTS: Neither imatinib nor nilotinib affected the magnitude of FMD (max dilation = 78±17% vehicle, 80 ± 24% nilotinib, 73 ± 13% imatinib). FMD was decreased by L-NAME in vehicle-treated arterioles (max dilation = 47±29%). Conversely, L-NAME had no effect on FMD in imatinib- or nilotinib-treated vessels (max dilation = 79±14% and 80 ± 24%, respectively), rather FMD was inhibited by PEG-Catalase (max dilation = 29±11% and 29 ± 14%, respectively).
CONCLUSION: Incubating human arterioles with imatinib or nilotinib switches the mediator of FMD from vasoprotective nitric oxide to pro-inflammatory H2 O2 .
Author List
Durand MJ, Hader SN, Derayunan A, Zinkevich N, McIntosh JJ, Beyer AMAuthors
Andreas M. Beyer PhD Associate Professor in the Medicine department at Medical College of WisconsinJennifer Jury Mcintosh DO Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAged
Antineoplastic Agents
Arterioles
Cardiotonic Agents
Catalase
Enzyme Inhibitors
Female
Fusion Proteins, bcr-abl
Humans
Hydrogen Peroxide
Imatinib Mesylate
In Vitro Techniques
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Male
Microvessels
Middle Aged
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Synthase
Polyethylene Glycols
Protein Kinase Inhibitors
Pyrimidines
Vasodilation
