BCR-ABL tyrosine kinase inhibitors promote pathological changes in dilator phenotype in the human microvasculature.

Abstract

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. Human adipose arterioles were incubated overnight in cell culture media containing vehicle (PBS), imatinib (10µmol/L) or nilotinib (100µmol/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 (100µmol/L) or the H2 O2 scavenger PEG-Catalase (500U/mL). 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). Incubating human arterioles with imatinib or nilotinib switches the mediator of FMD from vasoprotective nitric oxide to pro-inflammatory H2 O2 .