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Role of arginase in response to shear stress and cyclic stretch: potential new therapeutic target for atherosclerotic plaque vulnerability and vascular aging

English title Role of arginase in response to shear stress and cyclic stretch: potential new therapeutic target for atherosclerotic plaque vulnerability and vascular aging
Applicant Stergiopulos Nikolaos
Number 118274
Funding scheme Project funding (Div. I-III)
Research institution EPFL STI SGM-GE
Institution of higher education EPF Lausanne - EPFL
Main discipline Cardiovascular Research
Start/End 01.10.2007 - 30.09.2011
Approved amount 319'575.00
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Keywords (6)

hemodynamic forces; circumferential cyclic strain; wall shear stress; arginase pathway; vascular function and remodeling; atherosclerosis

Lay Summary (English)

Lead
Lay summary
Background: Atherosclerotic plaques are preferentially formed in curved areas of the vasculature, where shear stress is low (LSS), or near bifurcations, where shear stress is oscillatory (OSS, bi-directional). In contrast, relatively straight areas of the vasculature, characterized by high shear stress (HSS) values, are much less susceptible to develop early atherosclerotic plaques. Several risk factors for cardiovascular disease, including atherosclerosis, have been shown to induce the arginase pathway. Recently, it has been reported that higher arginase enzyme activity is involved in atherosclerotic endothelial dysfunction in apolipoprotein E-deficient mice. So far, the regulation of the arginases pathway by shear stress has not yet been investigated. Our preliminary results from ex vivo perfused artery showed that exposure of carotid segments to OSS and LSS conditions (athero-prone) significantly increase arginase II protein expression and activity as compared HSS flow conditions. Immunohistochemisty analysis confirmed a pronounced expression of arginase II on endothelial and smooth muscle cell. The relevance of these in vitro findings and new mechanisms need to be evaluated in vivo.Objectives: Our collaborators (Prof. Rob Krams and his team, Imperial College, UK) have recently developed and validated a highly innovative in vivo model of shear stress-induced atherogenesis in mice. By using this unique animal model, they could demonstrate that shear stress patterns not only predispose endothelium to plaque development but also determine the size of the lesion and its vulnerability. Therefore, we intend to use this mouse model to test our major hypothesis, which states that arginases play a key role in modulating shear stress-induced plaque formation and vulnerability in vivo. Methodology: Carotid arteries of ApoE-/- mice fed with high cholesterol diet will be exposed to different hemodynamic environments by the placement of shear stress-modifier device in the mice carotid for 9 weeks. A subgroup of animals will be chronically treated with arginase inhibitor in the presence or absence of L-arginine supplement. Endothelial function will be determined by organ chamber experiments in response to vasoactive compounds. Arginase gene expression will be determined by RT-PCR, protein expression by immunohistochemistry and its activity by the colorimetric determination of urea. Characterization of the atherosclerotic lesions induced by shear stress will be analyzed by histopathology.Potential significance: These studies shed light into the mechanisms of the pro-atherogenic properties of different shear stress patterns and in their modulation in the process of atherosclerotic plaques formation. This in vivo model will allow for the first time the evaluation of the relevance of the arginase pathway in the formation of both stable and vulnerable plaques. Most importantly, these studies can identify critical targets involved in the early phases of plaque development as well as in the stabilization of vulnerable plaque that may represent new approaches for atherosclerosis therapy.
Direct link to Lay Summary Last update: 21.02.2013

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