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This version published online on September 12, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0299
A more recent version of this article appeared on November 1, 2006
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Submitted on February 9, 2006
Accepted on August 29, 2006

DIRECT DEMONSTRATION OF AN ANTI-INFLAMMATORY EFFECT OF SIMVASTATIN IN SUBJECTS WITH THE METABOLIC SYNDROME

Sridevi Devaraj PhD, Emily Chan MD, and Ishwarlal Jialal MD, PhD*

Laboratory for Atherosclerosis and Metabolic Research, UCDavis Medical Center, and Veterans Affairs Medical Center, Sacramento, CA

* To whom correspondence should be addressed. 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 (HMG Co-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: To test the effect of simvastatin (40 mg/day) compared with placebo on biomarkers of inflammation [hsCRP, and monocytic cytokines (tumor necrosis factor-{alpha}, TNF, interleukin-6, IL-6 and interleukin-1{beta}, IL-1)] in MS subjects.

Design: Randomized, double-blind, placebo-controlled study

Setting: UCDavis Medical Center

Participants: Subjects with MS.

Intervention: Simvastatin (40 mg/day) or placebo for 8 weeks

Methods and Results: HsCRP levels were assayed using a high sensitivity immunoassay. Monocyte cytokines were assayed by ELISA following 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 LPS-activated monocytic release of IL-6 and TNF (P < 0.025). Simvastatin therapy significantly decreased NF{kappa}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 PI3K inhibitor or Rho kinase inhibitor. Lovastatin, significantly decreased Rho kinase and NF{kappa}B activity, significantly increased Akt activity and resulted in decreased monocyte IL-6 levels; these effects were reversed with mevalonate and geranylgeranylpyrophosphate indicating direct effects of statins on protein prenylation.

Conclusions: Thus, we show a direct anti-inflammatory effect of simvastatin therapy in MS. These findings could partly explain the benefit of statin therapy in these patients.
Key words: statin • monocytes • inflammation • CRP • pleiotropism




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