Rapamycin modulates the eNOS vs. shear stress relationship

被引:63
作者
Cheng, Caroline [1 ]
Tempel, Dennie [1 ]
Oostlander, Angela [2 ]
Helderman, Frank [1 ]
Gijsen, Frank [1 ]
Wentzel, Jolanda [1 ]
van Haperen, Rien [2 ]
Haitsma, David B. [1 ]
Serruys, Patrick W. [1 ]
van der Steen, Anton F. W. [1 ]
de Crom, Rini [2 ,3 ]
Krams, Rob [1 ,4 ]
机构
[1] Erasmus Univ, Med Ctr, Dept Cardiol, Ctr Thorax, Rotterdam, Netherlands
[2] Erasmus Univ, Med Ctr, Dept Cell Biol & Genet, Rotterdam, Netherlands
[3] Erasmus Univ, Med Ctr, Dept Vasc Surg, Rotterdam, Netherlands
[4] Univ London Imperial Coll Sci Technol & Med, Dept Bioengn, London SW7 2AZ, England
关键词
shear stress; rapamycin; atherosclerosis; C57BL6;
D O I
10.1093/cvr/cvm103
中图分类号
R5 [内科学];
学科分类号
1002 [临床医学]; 100201 [内科学];
摘要
Aims Studies in animals and patients indicate that rapamycin affects vasodilatation differently in outer and inner curvatures of blood vessels. We evaluated in this study whether rapamycin affects endothelial nitric oxide synthase (eNOS) responsiveness to shear stress under normo- and hypercholesteratemic conditions to explain these findings. Methods and results Shear stress levels were varied over a large range of values in carotid arteries of transgenic mice expressing human eNOS fused to enhanced green fluorescence protein. The mice were divided into control, low-dose rapamycin (3 mu g/kg/day), and high-dose rapamycin (3 mg/kg/day) groups and into normocholesteraemic and hypercholesteraemic (ApoE-/- on high cholesterol diet for 3-4 weeks) groups. The effect of rapamycin treatment on eNOS was evaluated by quantification of eNOS expression and of intracellular protein levels by en face confocal microscopy. A sigmoid curve fit was used to described these data. The efficacy of treatment was confirmed by measurement of rapamycin serum levels (2.0 +/- 0.5 ng/mL), and of p27(kiP1) expression in vascular tissue (increased by 2.4 +/- 0.5-fold). In control carotid arteries, eNOS expression increased by 1.8 +/- 0.3-fold in response to rapamycin. In the treated vessels, rapamycin reduced maximal eNOS expression at high shear stress levels (>5 Pa) in a dose-dependent way and shifted the sigmoid curve to the right. Hypercholesteraemia had a tendency to increase the leftward shift and the reduction in maximal. eNOS expression (P = 0.07). Conclusion Rapamycin is associated with high eNOS in low shear regions, i.e. in atherogenic regions, protecting these regions against atherosclerosis, and is associated with a reduction of eNOS at high shear stress affecting vasomotion in these regions.
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页码:123 / 129
页数:7
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