Contribution of arginase activation to vascular dysfunction in cigarette smoking

Gautam Sikka, Deepesh Pandey, Anil K. Bhuniya, Jochen Steppan, Dinani Armstrong, Lakshmi Santhanam, Daniel Nyhan, Dan E. Berkowitz

Research output: Contribution to journalArticlepeer-review

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, 6h/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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)91-94
Number of pages4
JournalAtherosclerosis
Volume231
Issue number1
DOIs
StatePublished - Nov 1 2013

Keywords

  • Arginase
  • Cholinergic response
  • Cigarette smoking
  • Endothelial dysfunction
  • Nitric oxide
  • ROS
  • Second hand smoke
  • Superoxide
  • Vascular stiffness
  • Vasodilation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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