The Effect of Mycophenolate Mofetil on Disease Development in the gld.apoE−/− Mouse Model of Accelerated Atherosclerosis and Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by autoantibody production and inflammatory disease involving multiple organs. Premature atherosclerosis is a common complication of SLE and results in substantial morbidity and mortality from cardiovascular disease (CVD). The reasons for the premature atherosclerosis in SLE are incompletely understood, although chronic inflammation is thought to play an important role. There is currently no known preventative treatment of premature atherosclerosis in SLE. Mycophenolate mofetil (MMF) is an immunosuppressive agent that is commonly used for treatment of patients with SLE. In order to study the impact of this drug on murine lupus disease including premature atherosclerosis development, we treated gld.apoE−/− mice, a model of SLE and accelerated atherosclerosis, with MMF. We maintained seven-week old gld.apoE−/− mice on a high cholesterol Western diet with or without MMF. After 12 weeks on diet, mice receiving MMF showed decreased atherosclerotic lesion area compared to the control group. MMF treatment also improved the lupus phenotype, indicated by a significant decrease circulating autoantibody levels and ameliorating lupus nephritis associated with this model. This data suggests that the effects of MMF on the immune system may not only be beneficial for lupus, but also for inflammation driving lupus-associated atherosclerosis.

Artesunate inhibits type I interferon-induced production of macrophage migration inhibitory factor in patients with systemic lupus erythematosus

“…Unfortunately, routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients (30). With the exception of mycophenolate mofetil and hydroxychloroquine (31;32), the availability of beneficial treatments to treat SLE-associated atherosclerosis is greatly limited. Since MIF plays an important role in the progression of atherosclerosis, the design of new inhibitors targeting MIF and the study of their effects on the biologic functions of this factor will be extremely valuable and promising for treatment of lupus atherosclerosis (23).…”

Why are kids with lupus at an increased risk of cardiovascular disease?

“…The immunomodulating effects of MMF limit its use as an atherosclerotic agent in the general population but are intriguing in patients with SLE. In mouse models of accelerated atherosclerosis and SLE, MMF decreased the severity of atherosclerosis while improving nephritis and inhibiting the development of autoantibodies [164]. Similarly, lupus-prone LDLr-null mice treated with MMF showed a significant decrease in the number of CD4+ T cells in atherosclerotic lesions despite no change in serum LDL [163].…”

Progression of noncalcified and calcified coronary plaque by CT angiography in SLE

“…These seven-week old mice were given a high-cholesterol Western diet for twelve weeks, with or without mycophenolate mofetil. Decreased atherosclerosis and decreased lupus phenotype were seen in the mice receiving mycophenolate mofetil, compared to controls [36]. …”