Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr-/- mice
| Autor: | John J.P. Kastelein, Sander I. van Leuven, Paul P. Tak, Yanice V. Mendez-Fernandez, Ashley J. Wilhelm, Nekeithia S. Wade, Amy S. Major, Curtis L. Gabriel, Erik S.G. Stroes |
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| Přispěvatelé: | Clinical Immunology and Rheumatology, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
CD4-Positive T-Lymphocytes
medicine.medical_specialty Lymphocyte Atorvastatin Immunology Population Drug Evaluation Preclinical Article General Biochemistry Genetics and Molecular Biology Mycophenolic acid Mice chemistry.chemical_compound Rheumatology immune system diseases Internal medicine medicine Animals Lupus Erythematosus Systemic Immunology and Allergy Genetic Predisposition to Disease Pyrroles education skin and connective tissue diseases Immunity Cellular education.field_of_study Systemic lupus erythematosus Lupus erythematosus Cholesterol business.industry Mycophenolic Acid Atherosclerosis medicine.disease Mice Inbred C57BL Disease Models Animal Interleukin 10 medicine.anatomical_structure Endocrinology chemistry Heptanoic Acids Drug Therapy Combination Female lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors business Immunosuppressive Agents medicine.drug |
| Zdroj: | Annals of the rheumatic diseases, 71(3), 408-414. BMJ Publishing Group |
| ISSN: | 0003-4967 |
| DOI: | 10.1136/annrheumdis-2011-200071 |
| Popis: | RationaleRecent clinical and preclinical studies have demonstrated that systemic lupus erythematosus (SLE) is associated with an increased risk for cardiovascular disease (CVD). However, unlike in the general population, little is known regarding the efficacy of atheroprotective interventions in patients with SLE. The current study aims to determine the benefit of lymphocyte inhibition on reducing the atherosclerotic burden in SLE-susceptible LDLr-deficient mice.MethodsFemale LDLr−/− mice were lethally irradiated and reconstituted with bone marrow from C57Bl/6 mice (LDLr.B6) or the SLE-susceptible B6.Sle1.2.3 mice (LDLr.Sle). At 16 weeks post transplant, mice were treated with atorvastatin (10 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or both (MMF-A) for 8 weeks, after which the extent of atherosclerosis and the presence of SLE were assessed.ResultsFollowing 8 weeks of treatment, we observed that atorvastatin-mediated reduction in cholesterol levels attenuated atherogenesis in LDLr.B6 mice but failed to significantly reduce atherosclerotic lesion size in LDLr.Sle mice, in spite of a significant reduction in serum cholesterol levels. Treatment with MMF and MMF-A attenuated atherogenesis in LDLr.B6 and LDLr.Sle mice. In addition, MMF-containing regimens inhibited recruitment of CD4+ T cells to atherosclerotic lesions in LDLr.Sle mice. In these mice, MMF also reduced the proportion of activated splenic T cells, as well as interleukin 10 secretion by T cells. With regard to lupus activity, MMF had no overt effect on anti-double-stranded DNA (dsDNA) antibody titres or kidney function and pathology.ConclusionsThe current study demonstrates that reduction of cholesterol levels alone is not atheroprotective in lupus-mediated atherogenesis. This is the first study to demonstrate that MMF reduces the atherosclerotic burden in a model of lupus-accelerated atherosclerosis. Our results suggest that MMF treatment may prove beneficial in preventing CVD in patients with SLE. |
| Databáze: | OpenAIRE |
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