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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

  • Xiong, Yuyan Vascular Biology, Department of medicine, Division of physiology, Faculty of science, University of Fribourg, Switzerland
  • Yu, Yi Vascular Biology, Department of medicine, Division of physiology, Faculty of science, University of Fribourg, Switzerland
  • Montani, Jean-Pierre Vascular Biology, Department of medicine, Division of physiology, Faculty of science, University of Fribourg, Switzerland
  • Yang, Zhihong Vascular Biology, Department of medicine, Division of physiology, Faculty of science, University of Fribourg, Switzerland
  • Ming, Xiu‐Fen Vascular Biology, Department of medicine, Division of physiology, Faculty of science, University of Fribourg, Switzerland
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    23.08.2013
Published in:
  • Journal of the American Heart Association. - 2013, vol. 2, no. 4, p. e000096
apoptosis
arginase
p53
p66Shc
vascular smooth muscle cells
English 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.Methods and 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.
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Biological sciences
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/303309
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