Journal
ANNALS OF BIOMEDICAL ENGINEERING
Volume 39, Issue 1, Pages 402-413Publisher
SPRINGER
DOI: 10.1007/s10439-010-0145-9
Keywords
Kruppel-like factor 2; Endothelial nitric oxide synthase; Thrombomodulin; Statins; Atherosclerosis
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Funding
- National Research Council of Canada (NSERC)
- les Fonds Quebecois de la Recherche sur la Nature et les Technologies (FQRNT)
- Canadian Institutes of Health Research (CIHR)
- William Dawson Fund
- McGill Engineering Doctoral Award (MEDA)
- Canadian Foundation for Innovation (CFI)
- Eugenie Ulmer Lamothe Fund (EUL)
- Vadasz Family Foundation
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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 mu M) 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 mu M), the combination of statin and unidirectional steady or pulsatile flow produced an overall additive increase in mRNA levels. At higher simvastatin concentration (10 mu M), 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 mu M. A higher simvastatin concentration of 10 mu M 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.
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