Arginase II Promotes Macrophage Inflammatory Responses Through Mitochondrial Reactive Oxygen Species, Contributing to Insulin Resistance and Atherogenesis

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

doi:10.1161/JAHA.112.000992

Arginase II Promotes Macrophage Inflammatory Responses Through Mitochondrial Reactive Oxygen Species, Contributing to Insulin Resistance and Atherogenesis

J Am Heart Assoc. 2012 Aug;1(4):e000992. doi: 10.1161/JAHA.112.000992. Epub 2012 Aug 24.

Authors

Xiu-Fen Ming¹, Angana G Rajapakse, Gautham Yepuri, Yuyan Xiong, João M Carvas, Jean Ruffieux, Isabelle Scerri, Zongsong Wu, Katja Popp, Jianhui Li, Claudio Sartori, Urs Scherrer, Brenda R Kwak, Jean-Pierre Montani, Zhihong Yang

Affiliation

¹ Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, Faculty of Science, University of Fribourg, Switzerland (X.-F.M., A.G.R., G.Y., Y.X., J.M.C., J.R., I.S., Z.W., K.P., J.-P.M., Z.Y.).

Abstract

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. (J Am Heart Assoc. 2012;1:e000992 doi: 10.1161/JAHA.112.000992.).

Keywords: atherosclerosis; diabetes mellitus, type 2; inflammation; macrophages.