title: Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr(-/-) mice.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Medicine/Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. s.i.vanleuven@amc.uva.nl
authors.forename: Sander I
authors.initials: SI
authors.lastname: van Leuven
authors.forename: Yanice V
authors.initials: YV
authors.lastname: Mendez-Fernandez
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Wilhelm
authors.forename: Nekeithia S
authors.initials: NS
authors.lastname: Wade
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Gabriel
authors.forename: John J
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Erik S
authors.initials: ES
authors.lastname: Stroes
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.forename: Amy S
authors.initials: AS
authors.lastname: Major
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000069059:Atorvastatin; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D020022:Genetic Predisposition to Disease; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007111:Immunity, Cellular / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use*
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D009173:Mycophenolic Acid