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J Clin Endocrinol Metab. 2006 Nov;91(11):4489-96. Epub 2006 Sep 12.

Direct demonstration of an antiinflammatory effect of simvastatin in subjects with the metabolic syndrome.

Author information

1
Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis, Medical Center and Veterans Affairs Medical Center, Sacramento, California 95817, USA.

Abstract

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-kappaB 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-kappaB 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.

PMID:
16968805
DOI:
10.1210/jc.2006-0299
[Indexed for MEDLINE]

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