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Simvastatin treatment ameliorates autoimmune disease associated with accelerated atherosclerosis in a murine lupus
Tamar Aprahamian1, Ramon Bonegio, Jennifer Rizzo
1Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
Insights
Simvastatin, a cholesterol-lowering drug, reduces atherosclerosis and lupus-like symptoms in mice by decreasing inflammation, not by lowering cholesterol. These findings suggest statins may treat autoimmune diseases like lupus.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Pharmacology
Background:
- Systemic lupus erythematosus (SLE) patients experience accelerated atherosclerosis, independent of traditional risk factors.
- 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) possess anti-inflammatory properties beyond cholesterol reduction.
- The gld.apoE-/- mouse model exhibits accelerated atherosclerosis and lupus-like features.
Purpose of the Study:
- To investigate the effects of simvastatin on atherosclerosis and lupus-like disease manifestations in gld.apoE-/- mice.
- To determine if simvastatin's effects are mediated by cholesterol reduction or anti-inflammatory actions.
Main Methods:
- Mice (wild-type, gld, apoE-/-, gld.apoE-/-) were fed a high-cholesterol diet and treated with simvastatin or saline for 12 weeks.
- Evaluated serum cholesterol, atherosclerotic lesion area, lymphadenopathy, renal disease, and cytokine production.
- Assessed STAT6/STAT4 induction and cytokine transcript levels in lymph nodes.
Main Results:
- Simvastatin did not alter serum cholesterol levels.
- Simvastatin significantly reduced atherosclerotic lesion area in apoE-/- and gld.apoE-/- mice.
- Simvastatin ameliorated lymphadenopathy, renal disease, and pro-inflammatory cytokine production in gld.apoE-/- mice.
- Simvastatin induced a shift from Th1 to Th2 immune response, evidenced by altered STAT signaling and cytokine profiles.
Conclusions:
- HMG-CoA reductase inhibitors like simvastatin can ameliorate atherosclerosis and lupus-like autoimmunity independently of cholesterol-lowering effects.
- The anti-inflammatory actions of statins, via a Th1 to Th2 shift, may offer therapeutic benefits for SLE patients with autoimmunity and atherosclerosis.
Abstract:
Patients with systemic lupus erythematosus develop accelerated atherosclerosis independent of traditional risk factors. The 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors are widely prescribed for hyperlipidemia, but they also exhibit anti-inflammatory actions that appear to be independent of their suppressive actions on plasma cholesterol levels. In this study, we analyzed the effect of the HMG-CoA reductase inhibitor simvastatin on disease manifestations in gld.apoE-/- mice that lack functional Fas ligand and apolipoprotein E and exhibit accelerated atherosclerosis and aggravated lupus-like features. Wild-type, gld, apoE-/-, and gld.apoE-/- mice were maintained on a high cholesterol Western diet and received daily simvastatin (0.125 mg/kg) or saline for 12 wk. Serum cholesterol levels were unaffected by simvastatin treatment, but atherosclerotic lesion area was reduced in both apoE-/- and gld.apoE-/- mice treated with simvastatin. Simvastatin also reduced the lymphadenopathy, renal disease, and proinflammatory cytokine production seen in gld.apoE-/-, but not gld, mice. The immunomodulatory effects in gld.apoE-/- mice were associated with enhanced STAT6 and decreased STAT4 induction in submandibular lymph node cells. Along with reductions in serum TNF-alpha and IFN-gamma levels, there was also an increase in IL-4 and IL-10 transcript levels in lymph nodes. These data indicate that HMG-CoA reductase inhibitors ameliorate atherosclerosis and lupus-like autoimmunity independent of their cholesterol-lowering effects via a shift from a Th1 to a Th2 phenotype in the gld.apoE-/- model. Thus, the anti-inflammatory activities of statins may have utility for the treatment of both autoimmunity and atherosclerosis in patients with systemic lupus erythematosus.
