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Simvastatin Treatment Ameliorates Autoimmune Disease Associated with Accelerated Atherosclerosis in a Murine Lupus Model¹

Tamar Aprahamian^*, Ramon Bonegio, Jennifer Rizzo^*, Harris Perlman, David J. Lefer, Ian R. Rifkin and Kenneth Walsh^2,*

^* Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118; Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Department of Molecular Microbiology and Immunology, Saint Louis University Medical School, St. Louis, MO 63104; and Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY 10469

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- and IFN- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AG15052, HL77774, HL81587, and AR40197 (to K.W.). T.A. was supported by a National Heart, Lung, and Blood Institute postdoctoral research training fellowship.

² Address correspondence and reprint requests to Dr. Kenneth Walsh, Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118. E-mail address: kxwalsh{at}bu.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; LDL, low-density lipoprotein; ANA, anti-nuclear Ab; HMG-CoA, 3-hydroxy-3-methyl-glutaryl coenzyme A; wt, wild type.

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