title: Contribution of arginase activation to vascular dysfunction in cigarette smoking.
abstract: BACKGROUND
  Cigarette smoke increases the risk of several cardiovascular diseases and has synergistic detrimental effects when present with other risks that contribute to its pathogenesis. Oxidative injury to the endothelium via reactive oxygen species (ROS) and nitric oxide (NO) dysregulation is a common denominator of smoking-induced alterations in vascular function. However, the mechanisms underlying ROS and NO dysregulation due to smoking remain unclear. We tested if arginase (Arg) activation/upregulation contributes to this phenomenon by constraining nitric oxide synthase (NOS) activity.
  
  
  METHODS
  Arg2 knockout (Arg2(-/-)) and control C57BL/6J mice were either exposed to cigarette smoke, 6 h/day/2 weeks (Second Hand Smoking; SHS) or housed in normal environment (Non Smoking; NS). Arg activity, NO and ROS levels were determined by measuring urea production, fluorescent dye (DAF), and dihydroethedium (DHE) respectively in isolated mouse aorta.
  
  
  RESULTS
  Arg activity and ROS levels were higher NO lower in SHS compared to NS mice. SHS failed to lower NO levels in Arg2(-/-) mice. Endothelial dependent vasodilation (EDV) was attenuated in SHS mice as compared to controls (78.80% ± 8 vs 46.58% ± 5). This impaired EDV was abolished in Arg2(-/-) mice (67.48% ± 7 in SHS vs. 78.80% ± 8 in NS). Vascular stiffness was increased in SHS mice as compared to NS controls but remained unchanged in Arg2(-/-) mice.
  
  
  CONCLUSIONS
  Endothelial NOS is uncoupled by smoking exposure, leading to endothelial dysfunction and vascular stiffness, a process that is prevented by Arg2 deletion. Hence, we identify Arg2 upregulation as a critical pathogenic factor and target for therapy in oxidative injury following smoking exposure through reciprocal regulation of endothelial NOS.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA. Electronic address: gsikka1@jhmi.edu.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sikka
authors.forename: Deepesh
authors.initials: D
authors.lastname: Pandey
authors.forename: Anil K
authors.initials: AK
authors.lastname: Bhuniya
authors.forename: Jochen
authors.initials: J
authors.lastname: Steppan
authors.forename: Dinani
authors.initials: D
authors.lastname: Armstrong
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
authors.forename: Daniel
authors.initials: D
authors.lastname: Nyhan
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001119:Arginase / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004789:Enzyme Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000097:blood*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000097:blood; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D059289:Vascular Stiffness / Q000187:drug effects
chemical_list: D017382:Reactive Oxygen Species; D014028:Tobacco Smoke Pollution; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C481673:Arg2 protein, mouse; D001119:Arginase
keywords: Arginase; Cholinergic response; Cigarette smoking; Endothelial dysfunction; Nitric oxide; ROS; Second hand smoke; Superoxide; Vascular stiffness; Vasodilation