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Arginase iI promotes macrophage inflammatory responses through mitochondrial reactive oxygen species, contributing to insulin resistance and atherogenesis

  • Ming, Xiu‐Fen Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Rajapakse, Angana G. Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Yepuri, Gautham Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Xiong, Yuyan Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Carvas, João M. Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Ruffieux, Jean Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Scerri, Isabelle Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Wu, Zongsong Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Popp, Katja Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Li, Jianhui Department of Intensive Care Medicine, University Hospital Center and Faculty of Biology and Medicine, Lausanne, Switzerland - Department of Hepatobiliary and Pancreatic Surgery and Centre of Organ Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  • Sartori, Claudio Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  • Scherrer, Urs Department of Cardiology, University Hospital, Bern, Switzerland - Facultad de Ciencias, Departamento de Biología, Universidad de Tarapacá, Arica, Chile
  • Kwak, Brenda R. Department of Pathology and Immunology, Department of Internal Medicine–Cardiology, University of Geneva, Switzerland
  • Montani, Jean-Pierre Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
  • Yang, Zhihong Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland
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    2012
Published in:
  • Journal of the American Heart Association. - 2012, vol. 1, no. 4, p. e000992
English Background Macrophage‐mediated chronic inflammation is mechanistically linked to insulin resistance and atherosclerosis. Although arginase I is considered antiinflammatory, the role of arginase II (Arg‐II) in macrophage function remains elusive. This study characterizes the role of Arg‐II in macrophage inflammatory responses and its impact on obesity‐linked type II diabetes mellitus and atherosclerosis.Methods and Results In human monocytes, silencing Arg‐II decreases the monocytes’ adhesion to endothelial cells and their production of proinflammatory mediators stimulated by oxidized low‐density lipoprotein or lipopolysaccharides, as evaluated by real‐time quantitative reverse transcription‐polymerase chain reaction and enzyme‐linked immunosorbent assay. Macrophages differentiated from bone marrow cells of Arg‐II–deficient (Arg‐II−/−) mice express lower levels of lipopolysaccharide‐induced proinflammatory mediators than do macrophages of wild‐type mice. Importantly, reintroducing Arg‐II cDNA into Arg‐II−/− macrophages restores the inflammatory responses, with concomitant enhancement of mitochondrial reactive oxygen species. Scavenging of reactive oxygen species by N‐acetylcysteine prevents the Arg‐II–mediated inflammatory responses. Moreover, high‐fat diet–induced infiltration of macrophages in various organs and expression of proinflammatory cytokines in adipose tissue are blunted in Arg‐II−/− mice. Accordingly, Arg‐II−/− mice reveal lower fasting blood glucose and improved glucose tolerance and insulin sensitivity. Furthermore, apolipoprotein E (ApoE)–deficient mice with Arg‐II deficiency (ApoE−/−Arg‐II−/−) display reduced lesion size with characteristics of stable plaques, such as decreased macrophage inflammation and necrotic core. In vivo adoptive transfer experiments reveal that fewer donor ApoE−/−Arg‐II−/− than ApoE−/−Arg‐II+/+ monocytes infiltrate into the plaque of ApoE−/−Arg‐II+/+ mice. Conversely, recipient ApoE−/−Arg‐II−/− mice accumulate fewer donor monocytes than do recipient ApoE−/−Arg‐II+/+ animals.Conclusions Arg‐II promotes macrophage proinflammatory responses through mitochondrial reactive oxygen species, contributing to insulin resistance and atherogenesis. Targeting Arg‐II represents a potential therapeutic strategy in type II diabetes mellitus and atherosclerosis
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Biological sciences
License
License undefined
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Persistent URL
https://folia.unifr.ch/unifr/documents/302415
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