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Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr−/− mice
  1. Sander I van Leuven1,2,3,
  2. Yanice V Mendez-Fernandez1,
  3. Ashley J Wilhelm1,
  4. Nekeithia S Wade4,
  5. Curtis L Gabriel4,
  6. John J Kastelein2,
  7. Erik S Stroes2,
  8. Paul P Tak3,
  9. Amy S Major1,4
  1. 1Department of Medicine/Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  2. 2Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
  3. 3Department of Clinical Immunology and Rheumatology, Academic Medical Center, Amsterdam, The Netherlands
  4. 4Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  1. Correspondence to Sander I Van Leuven, Academic Medical Center, Department of Vascular Medicine, Meibergdreef 9, 1100 DD, Amsterdam, The Netherlands; s.i.vanleuven{at}amc.uva.nl

Abstract

Rationale Recent 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.

Methods Female 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.

Results Following 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.

Conclusions The 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.

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Footnotes

  • Funding This work was supported by a fellowship from the International Atherosclerosis Society (SIL), American Heart Association Scientist Development Award (YVMF) and NIH grant R01HL088364 and R01HL089310 (to ASM).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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