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

Ming, Xiu‐Fen; Rajapakse, Angana G.; Yepuri, Gautham; Xiong, Yuyan; Carvas, João M.; Ruffieux, Jean; Scerri, Isabelle; Wu, Zongsong; Popp, Katja; Li, Jianhui; Sartori, Claudio; Scherrer, Urs; Kwak, Brenda R.; Montani, Jean-Pierre; Yang, Zhihong

doi:10.1161/JAHA.112.000992

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Journal article

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

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