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

Abstract

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 mu mol/L) or nilotinib (100 mu mol/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 mu mol/L) or the H(2)O(2)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 H2O2.