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

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.

• Authors: Sridevi Devaraj, Emily Chan, Ishwarlal Jialal
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 91 Issue 11 Pg. 4489-96 (Nov 2006) ISSN: 0021-972X [Print] United States
• PMID: 16968805 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Hypolipidemic Agents
• Interleukin-6
• NF-kappa B
• Placebos
• Tumor Necrosis Factor-alpha
• C-Reactive Protein
• Simvastatin
• Oncogene Protein v-akt

Topics

• Adult
• Anti-Inflammatory Agents (therapeutic use)
• C-Reactive Protein (analysis)
• Double-Blind Method
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Hypolipidemic Agents (therapeutic use)
• Inflammation (drug therapy)
• Interleukin-6 (blood)
• Male
• Metabolic Syndrome (drug therapy)
• Middle Aged
• Models, Biological
• Monocytes (drug effects)
• NF-kappa B (metabolism)
• Oncogene Protein v-akt (metabolism)
• Placebos
• Simvastatin (therapeutic use)
• Tumor Necrosis Factor-alpha (blood)