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Differential Response of Endothelial Cells to Simvastatin When Conditioned with Steady, Non-Reversing Pulsatile or Oscillating Shear Stress

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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.

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Acknowledgments

The authors would like to thank the National Research Council of Canada (NSERC), les Fonds Québécois de la Recherche sur la Nature et les Technologies (FQRNT), the Canadian Institutes of Health Research (CIHR), the William Dawson Fund, the McGill Engineering Doctoral Award (MEDA), the Canadian Foundation for Innovation (CFI), the Eugenie Ulmer Lamothe Fund (EUL), and the Vadasz Family Foundation for their financial support.

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Authors and Affiliations

  1. Department of Chemical Engineering, McGill University, 3610 University Street, Montreal, QC, H3A 2B2, Canada

    Joanna Rossi, Paul Jonak, Leonie Rouleau, Lisa Danielczak & Richard L. Leask

  2. Montreal Heart Institute, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada

    Joanna Rossi, Leonie Rouleau, Jean-Claude Tardif & Richard L. Leask

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  1. Joanna Rossi
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  2. Paul Jonak
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  3. Leonie Rouleau
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Correspondence to Richard L. Leask.

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Associate Editor Laura Suggs oversaw the review of this article.

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Rossi, J., Jonak, P., Rouleau, L. et al. Differential Response of Endothelial Cells to Simvastatin When Conditioned with Steady, Non-Reversing Pulsatile or Oscillating Shear Stress. Ann Biomed Eng 39, 402–413 (2011). https://doi.org/10.1007/s10439-010-0145-9

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