Arginase-I enhances vascular endothelial inflammation and senescence through eNOS-uncoupling.
BACKGROUND
Augmented arginase-II (Arg-II) is implicated in endothelial senescence and inflammation through a mutual positive regulatory circuit with S6K1. This study was conducted to investigate whether Arg-I, another isoform of arginase that has been also reported to play a role in vascular endothelial dysfunction, promotes endothelial senescence through similar mechanisms.


RESULTS
The non-senescent human endothelial cells from umbilical veins (passage 2 to 4) were transduced with empty recombinant adenovirus vector (rAd/CMV) as control or rAd/CMV-Arg-I to overexpress Arg-I. Overexpressing Arg-I promoted eNOS-uncoupling, enhanced senescence markers including p53-S15, p21 and senescence-associated β-galactosidase (SA-β-gal) staining, and increased inflammatory vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) as well as monocyte adhesion to endothelial cells without activating S6K1. All the effects of Arg-I were inhibited by the anti-oxidant N-acetylcysteine (NAC).


CONCLUSIONS
Our study demonstrates that Arg-I promotes endothelial senescence and inflammatory responses through eNOS-uncoupling unrelated to activation of the S6K1 pathway.
Cardiovascular and Aging Research, Division of Physiology, Department of Medicine, University of Fribourg, Chemin du Musée 5, 1700, Fribourg, Switzerland.
Cuicui
C
Zhu
Cardiovascular and Aging Research, Division of Physiology, Department of Medicine, University of Fribourg, Chemin du Musée 5, 1700, Fribourg, Switzerland.
Yi
Y
Yu
Cardiovascular and Aging Research, Division of Physiology, Department of Medicine, University of Fribourg, Chemin du Musée 5, 1700, Fribourg, Switzerland.|National Center of Competence in Research "Kidney.CH", University of Zürich, Zürich, Switzerland.
Jean-Pierre
JP
Montani
Cardiovascular and Aging Research, Division of Physiology, Department of Medicine, University of Fribourg, Chemin du Musée 5, 1700, Fribourg, Switzerland. xiu-fen.ming@unifr.ch.|National Center of Competence in Research "Kidney.CH", University of Zürich, Zürich, Switzerland. xiu-fen.ming@unifr.ch.
Xiu-Fen
XF
Ming
Cardiovascular and Aging Research, Division of Physiology, Department of Medicine, University of Fribourg, Chemin du Musée 5, 1700, Fribourg, Switzerland. zhihong.yang@unifr.ch.|National Center of Competence in Research "Kidney.CH", University of Zürich, Zürich, Switzerland. zhihong.yang@unifr.ch.
Zhihong
Z
Yang
D000111:Acetylcysteine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005822:Genetic Vectors / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016166:Free Radical Scavengers; D016159:Tumor Suppressor Protein p53; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D001616:beta-Galactosidase; C544448:Arg1 protein, mouse; D001119:Arginase; D000111:Acetylcysteine
Arginase-I; Endothelial cell; Inflammation; Senescence; eNOS-uncoupling