Simvastatin reduces the TLR4-induced inflammatory response in human aortic valve interstitial cells

J Surg Res. 2018 Oct;230:101-109. doi: 10.1016/j.jss.2018.04.054. Epub 2018 May 25.


Background: Calcific aortic stenosis is a chronic inflammatory disease. Proinflammatory stimulation via toll-like receptor 4 (TLR4) causes the aortic valve interstitial cell (AVIC) to undergo phenotypic change. The AVIC first assumes an inflammatory phenotype characterized by the production of inflammatory mediators such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). This change has been linked with an osteogenic phenotypic response. Statins have recently been shown to have anti-inflammatory properties. We therefore hypothesized that statins may have an anti-inflammatory effect on human AVICs by downregulation of TLR4-stimulated inflammatory responses. Our purposes were (1) to determine the effect of simvastatin on TLR4-induced expression of inflammatory mediators in human AVICs and (2) to determine the mechanism(s) through which simvastatin exert this effect.

Materials and methods: Human AVICs were isolated from the explanted hearts of four patients undergoing cardiac transplantation. Cells were treated with simvastatin (50 μM) for 1 h before stimulation with TLR4 agonist lipopolysaccharide (LPS, 0.2 μg/mL). Immunoblotting (IB) was used to analyze cell lysates for ICAM-1 expression, and enzyme-linked immunosorbent assay was used to detect IL-8 and MCP-1 in cell culture media. Likewise, lysates were analyzed for TLR4 and nuclear factor-kappa B activation (IB). After simvastatin treatment, lysates were analyzed for TLR4 levels (IB). Statistics were by analysis of variance (P < 0.05).

Results: Simvastatin reduced TLR4-induced ICAM-1, IL-8, and MCP-1 expression in AVICs. Simvastatin down-regulated TLR4 levels and suppressed TLR4-induced phosphorylation of nuclear factor-kappa B.

Conclusions: These data demonstrate the potential of a medical therapy (simvastatin) to impact the pathogenesis of aortic stenosis.

Keywords: Aortic stenosis; Statin; Valve interstitial cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aortic Valve / cytology
  • Aortic Valve / immunology
  • Aortic Valve / pathology*
  • Aortic Valve Stenosis / drug therapy*
  • Aortic Valve Stenosis / immunology
  • Aortic Valve Stenosis / pathology
  • Calcinosis / drug therapy*
  • Calcinosis / immunology
  • Calcinosis / pathology
  • Cardiomyopathy, Dilated / surgery
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Heart Transplantation
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Male
  • Middle Aged
  • Myofibroblasts
  • Primary Cell Culture
  • Simvastatin / pharmacology*
  • Simvastatin / therapeutic use
  • Toll-Like Receptor 4 / immunology*


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Simvastatin

Supplementary concepts

  • Aortic Valve, Calcification of