title: Arginase inhibition prevents the low shear stress-induced development of vulnerable atherosclerotic plaques in ApoE-/- mice.
abstract: OBJECTIVE
  Wall shear stress differentially regulates the arginase pathway in carotid arteries perfused ex vivo. Specific patterns of wall shear stress can locally determine atherosclerotic plaque size and composition in vivo. The present work investigates the effects of arginase inhibition on shear stress induced plaque composition.
  
  
  RESULTS
  Carotid arteries of apolipoprotein E deficient mice were exposed to high (HSS), low (LSS) and oscillatory (OSS) shear stress conditions by the placement of a local shear stress modifier device for 9 weeks with or without the administration of the arginase inhibitor N-ω-Hydroxy-nor-L-arginine (nor-Noha) (10 mg/kg, i.p., 5 days/week). Carotid arginase activity was measured by colorimetric determination of urea. Atherosclerotic plaque size and composition, arginase expression and cellular localization were assessed by immunohistochemistry. Arginase activity was significantly increased in both LSS and OSS regions as compared to HSS. In the lesions, arginase II isoform co-localized preferentially with EC. Inhibition of arginase by nor-Noha decreased arginase activity and reduced plaque size in both LSS and OSS regions. Arginase inhibition affected mainly the composition of plaques developed in LSS regions by decreasing the total vascular ROS, the number of macrophages, apoptosis rate, lipid and collagen contents.
  
  
  CONCLUSIONS
  Arginase activity is modulated by patterns of wall shear stress in vivo. Chronic inhibition of vascular arginase decreased the size of atherosclerotic lesions in both OSS and LSS regions, whereas changes on plaque composition were more pronounced in plaques induced by LSS. We identified wall shear stress as a key biomechanical regulator of arginase during plaque formation and stability.
authors: Department of Pharmacology, University of São Paulo, Ribeirão Preto, Brazil.
authors: Vania C
authors: VC
authors: Olivon
authors: Rodrigo A
authors: RA
authors: Fraga-Silva
authors: Dolf
authors: D
authors: Segers
authors: Céline
authors: C
authors: Demougeot
authors: Ana M
authors: AM
authors: de Oliveira
authors: Silvia S
authors: SS
authors: Savergnini
authors: Alain
authors: A
authors: Berthelot
authors: Rini
authors: R
authors: de Crom
authors: Rob
authors: R
authors: Krams
authors: Nikos
authors: N
authors: Stergiopulos
authors: Rafaela F
authors: RF
authors: da Silva
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D017209:Apoptosis; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism; D001696:Biomechanical Phenomena; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology*; D049109:Cell Proliferation; D003094:Collagen / Q000032:analysis; D006439:Hemodynamics; D008055:Lipids / Q000032:analysis; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D033081:Shear Strength; D013314:Stress, Mechanical; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; C404735:N(omega)-hydroxynorarginine; D017382:Reactive Oxygen Species; D003094:Collagen; D001120:Arginine; D001119:Arginase