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Direct Demonstration of an Antiinflammatory Effect of Simvastatin in Subjects with the Metabolic Syndrome

Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis, Medical Center, and Veterans Affairs Medical Center, Sacramento, California 95817

Address all correspondence and requests for reprints to: I. Jialal, M.D., Ph.D., Director, Laboratory for Atherosclerosis and Metabolic Research, 4635 II Avenue, Res 1 Building, Room 3000, University of California, Davis, Medical Center, Sacramento, California 95817. E-mail: ishwarlal.jialal{at}ucdmc.ucdavis.edu.

Context: Metabolic syndrome (MS) is characterized by low-grade inflammation and confers an increased risk for cardiovascular disease. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce cardiovascular events in MS patients. There is a paucity of data examining the effect of statins on inflammation in MS.

Objective: We aimed to test the effect of simvastatin (40 mg/d) compared with placebo on biomarkers of inflammation [high-sensitivity C-reactive protein (hsCRP) and monocytic cytokines TNF, IL-6, and IL-1] in MS subjects.

Design and Patients: We conducted a randomized, double-blind, placebo-controlled study at the University of California, Davis, Medical Center.

Participants: Participants were subjects with MS.

Intervention: Simvastatin (40 mg/d) or placebo was administered for 8 wk.

Methods and Results: The hsCRP levels were assayed using a high-sensitivity immunoassay. Monocyte cytokines were assayed by ELISA after activation with lipopolysaccharide. Simvastatin therapy significantly decreased hsCRP levels in MS subjects compared with placebo (P < 0.0005) and resulted in a significant reduction in plasma and lipopolysaccharide-activated monocytic release of IL-6 and TNF (P < 0.025). Simvastatin therapy significantly decreased nuclear factor-B and increased Akt activity in MS subjects compared with placebo. To gain mechanistic insights, human monocytes were pretreated with lovastatin with and without mevalonate or a phosphatidyl-3-kinase inhibitor or Rho kinase inhibitor. Lovastatin significantly decreased Rho kinase and nuclear factor-B activity, significantly increased Akt activity, and resulted in decreased monocyte IL-6 levels; these effects were reversed with mevalonate and geranylgeranyl pyrophosphate, indicating direct effects of statins on protein prenylation.

Conclusions: Thus, we show a direct antiinflammatory effect of simvastatin therapy in MS. These findings could partly explain the benefit of statin therapy in these patients.

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