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.

Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects

“…With respect to KLF2, researchers have also reported that atheroprotective laminar shear stress, through suppression of miR-92a, can upregulate endothelial TM via KLF2-dependent transactivation of the TM promoter (35, 187). Interestingly, the pleiotropic upregulation of endothelial TM by statins was only observed under atheroprotective shearing conditions (consistent with miR-92a suppression and KLF2 induction), and not under conditions of atherogenic oscillatory shear (128). These collective observations suggest that statinmediated pleiotropic effects on TM are restricted to shearprotected regions of the endothelium and putatively involve suppression of miR-92a.…”

Glycocalyx Degradation Induces a Proinflammatory Phenotype and Increased Leukocyte Adhesion in Cultured Endothelial Cells under Flow

“…Previous studies by our group have demonstrated the effectiveness in using these models to expose ECs to LSS [16,25–27,32–36]. Specifically, HAAECs were exposed to 10 dynes/cm 2 of LSS for 24 hours.…”

“…Detailed protocols for the 3D cell culture models and flow apparatus have been described previously [16,25–27]. Briefly, straight tube models (hemodynamic parameters within the model are summarized in Table 1) were made by mounting polished stainless steel rods into pre-designed molds.…”

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…Atorvastatin induced the vasculoprotective heme oxygenase-1 expression through the Akt pathway, mainly at sites of laminar stress (Ali et al, 2009a). Endothelial response to statins could be therefore affected by wall shear stress, because it has been recently observed that the protective action of simvastatin depends on the hemodynamic forces, being compromised by low shear stress with reversing flow (Rossi et al, 2011).…”