title: Arginase-II induces vascular smooth muscle cell senescence and apoptosis through p66Shc and p53 independently of its l-arginine ureahydrolase activity: implications for atherosclerotic plaque vulnerability.
abstract: BACKGROUND
  Vascular smooth muscle cell (VSMC) senescence and apoptosis are involved in atherosclerotic plaque vulnerability. Arginase-II (Arg-II) has been shown to promote vascular dysfunction and plaque vulnerability phenotypes in mice through uncoupling of endothelial nitric oxide synthase and activation of macrophage inflammation. The function of Arg-II in VSMCs with respect to plaque vulnerability is unknown. This study investigated the functions of Arg-II in VSMCs linking to plaque vulnerability.
  
  
  RESULTS
  In vitro studies were performed on VSMCs isolated from human umbilical veins, whereas in vivo studies were performed on atherosclerosis-prone apolipoprotein E-deficient (ApoE(-/-)) mice. In nonsenescent VSMCs, overexpressing wild-type Arg-II or an l-arginine ureahydrolase inactive Arg-II mutant (H160F) caused similar effects on mitochondrial dysfunction, cell apoptosis, and senescence, which were abrogated by silencing p66Shc or p53. The activation of p66Shc but not p53 by Arg-II was dependent on extracellular signal-regulated kinases (ERKs) and sequential activation of 40S ribosomal protein S6 kinase 1 (S6K1)-c-Jun N-terminal kinases (JNKs). In senescent VSMCs, Arg-II and S6K1, ERK-p66Shc, and p53 signaling levels were increased. Silencing Arg-II reduced all these signalings and cell senescence/apoptosis. Conversely, silencing p66Shc reduced ERK and S6K1 signaling and Arg-II levels and cell senescence/apoptosis. Furthermore, genetic ablation of Arg-II in ApoE(-/-) mice reduced the aforementioned signaling and apoptotic VSMCs in the plaque of aortic roots.
  
  
  CONCLUSIONS
  Arg-II, independently of its l-arginine ureahydrolase activity, promotes mitochondrial dysfunction leading to VSMC senescence/apoptosis through complex positive crosstalk among S6K1-JNK, ERK, p66Shc, and p53, contributing to atherosclerotic vulnerability phenotypes in mice.
authors.affiliation: Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Chemin du Musée 5, Fribourg, CH-1700, Switzerland.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Xiong
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Montani
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
authors.forename: Xiu-Fen
authors.initials: XF
authors.lastname: Ming
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D001119:Arginase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005838:Genotype; D006801:Humans; D006868:Hydrolysis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic; D034622:RNA Interference; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C477631:ARG2 protein, human; C481673:Arg2 protein, mouse; D001119:Arginase
keywords: apoptosis; arginase; p53; p66Shc; vascular smooth muscle cells