title: Differential response of endothelial cells to simvastatin when conditioned with steady, non-reversing pulsatile or oscillating shear stress.
abstract: Few studies have investigated whether fluid mechanics can impair or enhance endothelial cell response to pharmacological agents such as statin drugs. We evaluated and compared Kruppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and thrombomodulin (TM) expression in human abdominal aortic endothelial cells (HAAEC) treated with increasing simvastatin concentrations (0.1, 1 or 10 μM) under static culture and shear stress (steady, non-reversing pulsatile, and oscillating). Simvastatin, steady flow, and non-reversing pulsatile flow each separately upregulated KLF2, eNOS, and TM mRNA. At lower simvastatin concentrations (0.1 and 1 μM), the combination of statin and unidirectional steady or pulsatile flow produced an overall additive increase in mRNA levels. At higher simvastatin concentration (10 μM), a synergistic increase in eNOS and TM mRNA expression was observed. In contrast, oscillating flow impaired KLF2 and TM, but not eNOS expression by simvastatin at 1 μM. A higher simvastatin concentration of 10 μM overcame the inhibitory effect of oscillating flow. Our findings suggest that oscillating shear stress renders the endothelial cells less responsive to simvastatin than cells exposed to unidirectional steady or pulsatile flow. Consequently, the pleiotropic effects of statins in vivo may be less effective in endothelial cells exposed to atheroprone hemodynamics.
authors.affiliation: Department of Chemical Engineering, McGill University, 3610 University Street, Montreal, QC, H3A 2B2, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Rossi
authors.forename: Paul
authors.initials: P
authors.lastname: Jonak
authors.forename: Leonie
authors.initials: L
authors.lastname: Rouleau
authors.forename: Lisa
authors.initials: L
authors.lastname: Danielczak
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Richard L
authors.initials: RL
authors.lastname: Leask
mesh_terms: D000924:Anticholesteremic Agents / Q000008:administration & dosage; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000502:physiology*; D011673:Pulsatile Flow / Q000187:drug effects / Q000502:physiology*; D033081:Shear Strength / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000008:administration & dosage*; D013314:Stress, Mechanical
chemical_list: D000924:Anticholesteremic Agents; D019821:Simvastatin