title: The effect of simvastatin treatment on endothelial cell response to shear stress and tumor necrosis factor alpha stimulation.
abstract: BACKGROUND
  Statin drugs are one of the most commonly prescribed pharmaceuticals by physicians. By blocking the rate-limiting step in the cholesterol biosynthesis pathway, statins inhibit cholesterol synthesis, which benefits patient health. However, since many other important cellular processes are regulated within this pathway, they may also be influenced by statin therapy. These pleiotropic effects of statins have not been fully investigated, but are believed to positively influence endothelial cells (ECs), which line the vasculature in a confluent monolayer. Few studies have considered the effect of blood flow on ECs and how this may augment EC response to statins.
  
  
  METHODS
  In this study, the effect of statin treatment on ECs is investigated for cells stimulated with tumor necrosis factor alpha (TNF-α), an inflammatory cytokine that promotes an atheroprone endothelium. Additionally, ECs are exposed to a physiologically relevant wall shear stress (WSS) of 12.5 dynes/cm(2) using a three-dimensional tissue culture model to provide a realistic hemodynamic environment. ECs are analyzed for morphology using light microscopy as well as cytoskeletal structure and alignment using confocal microscopy. Statistical analysis is performed on the results using both the one-way analysis of variance with Bonferroni post-tests and the two-tailed t test.
  
  
  RESULTS
  We have shown that statin treatment caused cells to adapt to a rounded, atheroprone morphology, with a significantly higher shape index. Oppositely, TNF-α stimulation caused cells to elongate to an atheroprotective morphology, with a significantly lower shape index. WSS and TNF-α were unable to reverse any statin-induced cell rounding or F-actin disruption.
  
  
  CONCLUSIONS
  Further work is therefore needed to determine why statin drugs cause cells to have an atheroprone morphology, but an atheroprotective genotype, and why TNF-α stimulation causes an atheroprotective morphology, but an atheroprone genotype. Despite the morphological changes due to statins or stimulation, ECs still respond to WSS. Understanding how statins influence ECs will allow for more targeted treatments for hypercholestemia and potentially other diseases.
authors.affiliation: Department of Chemical Engineering, McGill University, 3610 University Avenue, Montreal, QC, H3A 2B2, Canada. melissa.dick@mail.mcgill.ca.|Montreal Heart Institute, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada. melissa.dick@mail.mcgill.ca.
authors.forename: Melissa
authors.initials: M
authors.lastname: Dick
authors.affiliation: Department of Chemical Engineering, McGill University, 3610 University Avenue, Montreal, QC, H3A 2B2, Canada. katherine.macdonald4@mail.mcgill.ca.
authors.forename: Katherine
authors.initials: K
authors.lastname: MacDonald
authors.affiliation: Montreal Heart Institute, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada. jean-claude.tardif@icm-mhi.org.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: Department of Chemical Engineering, McGill University, 3610 University Avenue, Montreal, QC, H3A 2B2, Canada. richard.leask@mcgill.ca.|Montreal Heart Institute, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada. richard.leask@mcgill.ca.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Leask
mesh_terms: D000199:Actins / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D019821:Simvastatin / Q000494:pharmacology*; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000199:Actins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin