title: Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages.
abstract: 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).
  
  
  OBJECTIVE
  To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Jelena
authors.initials: J
authors.lastname: Gacic
authors.affiliation: Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Emina
authors.initials: E
authors.lastname: Vorkapic
authors.affiliation: Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Laboratory Services, County Hospital Ryhov, Jönköping, Sweden.
authors.forename: Renate Slind
authors.initials: RS
authors.lastname: Olsen
authors.affiliation: Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Söderberg
authors.affiliation: Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Gustafsson
authors.affiliation: Genome Analytics Group, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Skoglund
authors.affiliation: Department of Laboratory Services, County Hospital Ryhov, Jönköping, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Matussek
authors.affiliation: Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Electronic address: dick.wagsater@liu.se.
authors.forename: Dick
authors.initials: D
authors.lastname: Wågsäter
mesh_terms: D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D002784:Cholesterol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Atherosclerosis; Cholesterol; Imatinib; Macrophages