mercaptopurine and Atherosclerosis

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder. Systemic inflammation increases the risk of atherosclerosis and ischaemic heart disease (IHD).. To examine the impact of IBD, including its duration and treatment, on the risk of IHD.. In a nationwide population-based cohort of 4.6 million Danes aged ≥ 15 years, we compared people diagnosed with IBD during 1997-2009 (n=28 833) with IBD-free individuals. Subjects with IHD were identified in the National Patient Register. Using Poisson regression, we estimated the incidence rate ratios (IRRs) for IHD with 95% CI with adjustment for age, gender, socioeconomic status, calendar year and use of drugs for comorbidities.. A markedly increased risk of IHD was seen within the first year after IBD diagnosis (IRR=2.13 95% CI 1.91 to 2.38). During 1-13 years of follow-up after IBD diagnosis, the risk of IHD was 1.22 (95% CI 1.14 to 1.30). The risk of IHD was lower among patients with IBD using 5-aminosalicylic acids (IRR=1.16; 95% CI 1.06 to 1.26) than among non-users (IRR=1.36; 95% CI 1.22 to 1.51) (p=0.02), in particular among oral corticosteroid users, used as a proxy for disease severity. Likewise patients treated surgically or with thiopurines and tumour necrosis factor α antagonists tended to have reduced IRRs for IHD.. The risk of IHD was highest in the first year after IBD diagnosis, possibly owing to ascertainment bias. The increased long-term risk of IHD in IBD may be related to chronic inflammation, and interventions reducing the inflammatory burden may attenuate this risk.

Topics: Adolescent; Adult; Aged; Atherosclerosis; Case-Control Studies; Cohort Studies; Denmark; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Male; Mercaptopurine; Mesalamine; Middle Aged; Myocardial Ischemia; Registries; Risk; Severity of Illness Index; Tumor Necrosis Factor-alpha

6-Mercaptopurine (6-MP), the active metabolite of the immunosuppressive prodrug azathioprine, is commonly used in autoimmune diseases and transplant recipients, who are at high risk for cardiovascular disease. Here, we aimed to gain knowledge on the action of 6-MP in atherosclerosis, with a focus on monocytes and macrophages.. We demonstrate that 6-MP induces apoptosis of THP-1 monocytes, involving decreased expression of the intrinsic antiapoptotic factors B-cell CLL/Lymphoma-2 (Bcl-2) and Bcl2-like 1 (Bcl-x(L)). In addition, we show that 6-MP decreases expression of the monocyte adhesion molecules platelet endothelial adhesion molecule-1 (PECAM-1) and very late antigen-4 (VLA-4) and inhibits monocyte adhesion. Screening of a panel of cytokines relevant to atherosclerosis revealed that 6-MP robustly inhibits monocyte chemoattractant chemokine-1 (MCP-1) expression in macrophages stimulated with lipopolysaccharide (LPS). Finally, local delivery of 6-MP to the vessel wall, using a drug-eluting cuff, attenuates atherosclerosis in hypercholesterolemic apolipoprotein E*3-Leiden transgenic mice (P<0.05). In line with our in vitro data, this inhibition of atherosclerosis by 6-MP was accompanied with decreased lesion monocyte chemoattractant chemokine-1 levels, enhanced vascular apoptosis, and reduced macrophage content.. We report novel, previously unrecognized atheroprotective actions of 6-MP in cultured monocytes/macrophages and in a mouse model of atherosclerosis, providing further insight into the effect of the immunosuppressive drug azathioprine in atherosclerosis.

Topics: Animals; Apolipoprotein E3; Apoptosis; Atherosclerosis; bcl-X Protein; Cell Adhesion; Cells, Cultured; Chemokine CCL2; Chemotaxis; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Inflammation Mediators; Integrin alpha4beta1; Macrophages; Male; Mercaptopurine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monocytes; Platelet Endothelial Cell Adhesion Molecule-1; Proto-Oncogene Proteins c-bcl-2; Time Factors

Topics: Animals; Apolipoprotein E3; Apoptosis; Atherosclerosis; bcl-X Protein; Cell Adhesion; Chemokine CCL2; Chemotaxis; Humans; Immunosuppressive Agents; Inflammation Mediators; Integrin alpha4beta1; Macrophages; Mercaptopurine; Mice; Monocytes; Platelet Endothelial Cell Adhesion Molecule-1; Proto-Oncogene Proteins c-bcl-2