title: Harmful effects of the azathioprine metabolite 6-mercaptopurine in vascular cells: induction of mineralization.
abstract: Vascular mineralization contributes to the high cardiovascular morbidity and mortality in patients who suffer from chronic kidney disease and in individuals who have undergone solid organ transplantation. The immunosuppressive regimen used to treat these patients appears to have an impact on vascular alterations. The effect of 6-mercaptopurine (6-MP) on vascular calcification has not yet been determined. This study investigates the effect of 6-MP on vascular mineralization by the induction of trans-differentiation of rat vascular smooth muscle cells in vitro. 6-MP not only induces the expression of osteo-chondrocyte-like transcription factors and proteins but also activates alkaline phosphatase enzyme activity and produces calcium deposition in in vitro and ex vivo models. These processes are dependent on 6-MP-induced production of reactive oxygen species, intracellular activation of mitogen-activated kinases and phosphorylation of the transcription factor Cbfa1. Furthermore, the metabolic products of 6-MP, 6-thioguanine nucleotides and 6-methyl-thio-inosine monophosphate have major impacts on cellular calcification. These data provide evidence for a possible harmful effect of the immunosuppressive drug 6-MP in vascular diseases, such as arteriosclerosis.
authors.affiliation: Charité - Universitaetsmedizin Berlin; Charité Centrum 13, Department of Nephrology Campus Benjamin Franklin, Berlin, Germany; Freie Universitaet Berlin, Fachbereich Biochemie, Chemie, Berlin, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Prüfer
authors.affiliation: Charité - Universitaetsmedizin Berlin; Charité Centrum 13, Department of Nephrology Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schuchardt
authors.affiliation: Charité - Universitaetsmedizin Berlin; Charité Centrum 13, Department of Nephrology Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Tölle
authors.affiliation: Charité - Universitaetsmedizin Berlin; Charité Centrum 13, Department of Nephrology Campus Benjamin Franklin, Berlin, Germany; Universitaet Potsdam, Department of Nutrition Science, Potsdam, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Prüfer
authors.affiliation: Novartis Germany GmbH, Nuernberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Höhne
authors.affiliation: Charité - Universitaetsmedizin Berlin; Charité Centrum 13, Department of Nephrology Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Zidek
authors.affiliation: Charité - Universitaetsmedizin Berlin; Charité Centrum 13, Department of Nephrology Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: van der Giet
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D001379:Azathioprine / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D018450:Disease Progression; D015122:Mercaptopurine / Q000378:metabolism* / Q000494:pharmacology*; D008903:Minerals / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008903:Minerals; D017382:Reactive Oxygen Species; D015122:Mercaptopurine; D001379:Azathioprine; D002118:Calcium