Journal article

Thrombin Stimulates Human Endothelial Arginase Enzymatic Activity via RhoA/ROCK Pathway

  • Ming, Xiu-Fen Department of Medicine, Division of Physiology University of Fribourg, Switzerland
  • Barandier, Christine Department of Medicine, Division of Physiology University of Fribourg, Switzerland
  • Viswambharan, Hema Department of Medicine, Division of Physiology University of Fribourg, Switzerland
  • Kwak, Brenda R. Division of Cardiology, University Hospital Geneva
  • Mach, François Division of Cardiology, University Hospital Geneva
  • Mazzolai, Lucia Division of Hypertension and Vascular Medicine, University Hospital, Lausanne, Switzerland
  • Hayoz, Daniel Division of Hypertension and Vascular Medicine, University Hospital, Lausanne, Switzerland
  • Ruffieux, Jean Department of Medicine, Division of Physiology University of Fribourg, Switzerland
  • Rusconi, Sandro Department of Medicine, Division of Biochemistry University of Fribourg, Switzerland
  • Montani, Jean-Pierre Department of Medicine, Division of Physiology University of Fribourg, Switzerland
  • Yang, Zhihong Department of Medicine, Division of Physiology University of Fribourg, Switzerland
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    29.11.2004
Published in:
  • Circulation. - 2004, vol. 110, no. 3708-3714
English Background— Arginase competes with endothelial nitric oxide synthase (eNOS) for the substrate L-arginine and decreases NO production. This study investigated regulatory mechanisms of arginase activity in endothelial cells and its role in atherosclerosis. Methods and Results— In human endothelial cells isolated from umbilical veins, thrombin concentration- and time-dependently stimulated arginase enzymatic activity, reaching a 1.9-fold increase (P<0.001) at 1 U/mL for 24 hours. The effect of thrombin was prevented by C3 exoenzyme or the HMG-CoA reductase inhibitor fluvastatin, which inhibit RhoA, or by the ROCK inhibitors Y-27632 and HA-1077. Adenoviral expression of constitutively active RhoA or ROCK mutants enhanced arginase activity (≈3-fold, P<0.001), and the effect of active RhoA mutant was inhibited by the ROCK inhibitors. Neither thrombin nor the active RhoA/ROCK mutants affected arginase II protein level, the only isozyme detectable in the cells. Moreover, a significantly higher arginase II activity (1.5-fold, not the protein level) and RhoA protein level (4-fold) were observed in atherosclerotic aortas of apoE–/– compared with wild-type mice. Interestingly, L-arginine (1 mmol/L), despite a significantly higher eNOS expression in aortas of apoE–/– mice, evoked a more pronounced contraction, which was reverted to a greater vasodilation by the arginase inhibitor L-norvaline (20 mmol/L) compared with the wild-type animals (n=5, P<0.001). Conclusions— Thrombin enhances arginase activity via RhoA/ROCK in human endothelial cells. Higher arginase enzymatic activity is involved in atherosclerotic endothelial dysfunction in apoE–/– mice. Targeting vascular arginase may represent a novel therapeutic possibility for atherosclerosis.
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Medicine
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/299618
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