Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages
2016 (English)In: Pharmacological Reports, ISSN 1734-1140, Vol. 68, no 1, 1-6 p.Article in journal (Refereed) PublishedText
Background: Imatinib mesylate (Glivec, formerly STI-571) is a selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, there are reports suggesting that imatinib could be atheroprotective by lowering plasma low-density lipoprotein (LDL). Aim: To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity. Methods and results: Uptake of fluorescence-labeled LDL was analyzed using flow cytometry. Macrophages treated with imatinib showed a 23.5%, 27%, and 15% decrease in uptake of native LDL (p < 0.05), acetylated LDL (p < 0.01), and copper-modified oxidized LDL (p < 0.01), respectively. Gel based zymography showed that secretion and activity of MMP-2 and MMP-9 were inhibited by imatinib. Using GeneChip Whole Transcript Expression array analysis, no obvious gene candidates involved in the mechanisms of cholesterol metabolism or MMP regulation were found to be affected by imatinib. Instead, we found that imatinib up-regulated microRNA 155 (miR155) by 43.8% and down-regulated ADAM metallopeptidase domain 28 (ADAM28) by 41.4%. Both genes could potentially play an atheroprotective role and would be interesting targets in future studies. Conclusion: Our results indicate that imatinib causes post-translational inhibition with respect to cholesterol uptake and regulation of MMP-2 and MMP-9. More research is needed to further evaluate the role of imatinib in the regulation of other genes and processes. (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
Place, publisher, year, edition, pages
POLISH ACAD SCIENCES INST PHARMACOLOGY , 2016. Vol. 68, no 1, 1-6 p.
Atherosclerosis; Cholesterol; Imatinib; Macrophages
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:liu:diva-125158DOI: 10.1016/j.pharep.2015.05.024ISI: 000368567800001PubMedID: 26721343OAI: oai:DiVA.org:liu-125158DiVA: diva2:903410
Funding Agencies|Swedish Research Council [K2013-99X-22231-01-5]2016-02-152016-02-152016-03-14