mercaptopurine and Arteriosclerosis

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.

Topics: Animals; Aorta; Arteriosclerosis; Azathioprine; Calcium; Disease Progression; Mercaptopurine; Minerals; Muscle, Smooth, Vascular; Phenotype; Rats; Rats, Wistar; Reactive Oxygen Species

Topics: Animals; Aorta; Arteriosclerosis; Histamine Antagonists; Hypercholesterolemia; Immunization; Male; Mercaptopurine; Rabbits; Serotonin Antagonists; Serum Albumin, Bovine

1. Effects of various drugs on cholesterol-induced atherosclerosis in rabbits during the progression phase have been studied. The drugs tested are antimetabolites (mercaptopurine, hydroxyurea), surface active agents (sodiumdodecyl sulfate), inhibitor of adrenocoritcal steroid synthesis (o, p'-DDD), lysosome stablizers (chloroquine, acetylsalicylic acid) with antihistaminic (chlorpheniramine) and cholesterol binder (nystatin). 2. Mercaptopurine treatment showed marekd reduction in both atherosclerotic lesions and cholesterol concentrations of the serum and aorta. 3. Hydroxyurea reduced both the aortic cholesterol concentration and the lesions, but the serum cholesterol concentration remained high. 4. Sodiumdodecyl sulfate and o, o'-DDD showed slight inhibition of the development of atherosclerosis. 5. Pyridinocarbamate showed a slight beneficial effect on the prevention of atherosclerosis only when it was administered prior to the meal. 6. Nystatin, chloroquine and acetylsalicylic acid + chlorpheniramine showed little effect.

Topics: Animals; Arteriosclerosis; Aspirin; Chloroquine; Cholesterol, Dietary; Clomipramine; Hydroxyurea; Male; Mercaptopurine; Pharmacology; Pyridinolcarbamate; Rabbits; Sodium Dodecyl Sulfate