Statins Disrupt Macrophage Rac1 Regulation Leading to Increased Atherosclerotic Plaque Calcification

Arterioscler Thromb Vasc Biol. 2020 Mar;40(3):714-732. doi: 10.1161/ATVBAHA.119.313832. Epub 2020 Jan 30.


Objective: Calcification of atherosclerotic plaque is traditionally associated with increased cardiovascular event risk; however, recent studies have found increased calcium density to be associated with more stable disease. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins reduce cardiovascular events. Invasive clinical studies have found that statins alter both the lipid and calcium composition of plaque but the molecular mechanisms of statin-mediated effects on plaque calcium composition remain unclear. We recently defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1β (interleukin-1 beta) signaling axis to be a key mechanism in promoting atherosclerotic calcification and sought to define the impact of statin therapy on this pathway. Approach and Results: Here, we demonstrate that statin therapy is independently associated with elevated coronary calcification in a high-risk patient population and that statins disrupt the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased active (GTP bound) Rac1 in primary monocytes/macrophages. Rac1 activation is prevented by rescue with the isoprenyl precursor geranylgeranyl diphosphate. Statin-treated macrophages exhibit increased activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), increased IL-1β mRNA, and increased Rac1-dependent IL-1β protein secretion in response to inflammasome stimulation. Using an animal model of calcific atherosclerosis, inclusion of statin in the atherogenic diet led to a myeloid Rac1-dependent increase in atherosclerotic calcification, which was associated with increased serum IL-1β expression, increased plaque Rac1 activation, and increased plaque expression of the osteogenic markers, alkaline phosphatase and RUNX2 (Runt-related transcription factor 2).

Conclusions: Statins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1-IL-1β signaling axis.

Keywords: animals; atherosclerosis; humans; inflammation; monocytes.

Publication types

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

MeSH terms

  • Aged
  • Animals
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / enzymology
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Atorvastatin / therapeutic use*
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Macrophages / drug effects*
  • Macrophages / enzymology
  • Macrophages / pathology
  • Male
  • Mice, Knockout, ApoE
  • Neuropeptides / deficiency
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Plaque, Atherosclerotic*
  • Prenylation
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Retrospective Studies
  • Signal Transduction
  • Vascular Calcification / enzymology*
  • Vascular Calcification / genetics
  • Vascular Calcification / pathology
  • rac1 GTP-Binding Protein / deficiency
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / metabolism


  • ARHGDIA protein, human
  • Csf1r protein, mouse
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • IL1B protein, human
  • IL1B protein, mouse
  • Interleukin-1beta
  • Neuropeptides
  • RAC1 protein, human
  • Rac1 protein, mouse
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • rho Guanine Nucleotide Dissociation Inhibitor alpha
  • Atorvastatin
  • rac1 GTP-Binding Protein