The tyrosine kinase inhibitor nilotinib targets discoidin domain receptor 2 in calcific aortic valve stenosis
article
Background and purpose: Tyrosine kinase inhibitors (TKI) used to treat chronic myeloid leukemia (CML) have been associated with cardiovascular side effects, including reports on calcific aortic valve stenosis. The aim of this study was to establish the effects of first and second generation TKIs in aortic valve stenosis, and to determine the associated molecular mechanisms EXPERIMENTAL APPROACH: Treatment of APOE*3Leiden.CETP transgenic mice with nilotinib, imatinib or vehicle. Isolation and stimulation of human valvular interstitial cells (VICs). Gene expression analysis of aortic valves from 64 patients undergoing aortic valve replacement surgery. Key results: Nilotinib increased murine aortic valve thickness. Nilotinib, but not imatinib, promoted calcification, osteogenic activation and decreased autophagy in human VICs. Differential tyrosine kinase expression was detected between healthy and calcified valve tissue. Transcriptomic target identification revealed that discoidin domain receptor (DDR) 2, which is preferentially inhibited by nilotinib, was predominantly expressed in human aortic valves but markedly downregulated in calcified valve tissue. Nilotinib and selective DDR2 targeting in VICs induced a similar osteogenic activation, which was blunted by increasing the DDR2 ligand, collagen. Conclusions & implications: These findings point to that inhibition of DDR2 by nilotinib promoted aortic valve thickening and VIC calcification, with possible translational implications for the cardiovascular surveillance and possible personalized medicine in CML patients.
Topics
TNO Identifier
972408
Source
British Journal of Pharmacology, 179(19), pp. 4709-4721.
Pages
4709-4721