Background: Alterations of wall shear stress can predispose the endothelium to the development of atherosclerotic plaques. We evaluated the modulation of arginase by wall shear stress. Material and methods: We perfused isolated carotid arterial segments to either unidirectional high mean shear stress (HSS) or low mean and oscillating shear stress (OSS) for 3 days. Vascular function was analyzed by diameter measurement, arginase expression and localization by western blot and immunohistochemistry, respectively. These effects were also evaluated in right carotid artery of apolipoprotein E (apoE-/-) deficient mice, fed with high cholesterol diet, which was exposed to HSS, LSS and OSS flow conditions by the placement of a shear stress modifier for 9 weeks. ApoE-/- mice received either the arginase inhibitor nor-Noha (20mg/kg, 5 days/week) or placebo for 9 weeks. Plaque size and I/M ratio were determined by histology. Results: Our data from ex vivo perfusion showed that exposure of carotid segments to both low and oscillatory flow conditions significantly increase arginase II protein expression and activity as compared to high shear stress athero-protective flow condition. Long-term treatment with nor-Noha effectively decreased arginase activity at LSS and OSS regions, which in turn was accompanied by a decreased I/M ratio and the size of atherosclerotic lesion. In the lesion, inhibition of arginase decreased the number of CD68 positive cells at LSS and OSS zones. Exposure of carotid artery to OSS induced a more pronounced activation of arginase as compared to HSS. Conclusions: Arginase is modulated by patterns of wall shear stress. Long-term treatment of apoE- /- mice with arginase inhibitor decreased carotid I/M ratio and atherosclerotic lesion at LSS and OSS regions. Therefore, inhibition of arginase by nor-Noha may emerge as a distinct way to target atherosclerosis disease.

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IFMBE Proceedings
Erasmus MC: University Medical Center Rotterdam

da Silva, R. F., Olivon, V. C., Segers, D., de Crom, R., Stergiopuloss, N., & Krams, R. (2010). Ex vivo and in vivo regulation of arginase in response to wall shear stress. In IFMBE Proceedings (Vol. 29, pp. 753–756). doi:10.1007/978-3-642-13039-7_190