Identification of Macrophage Arginase I as a New Candidate Gene of Atherosclerosis Resistance

Teupser, Daniel; Burkhardt, Ralph; Wilfert, Wolfgang; Haffner, Ivonne; Nebendahl, Klaus; Thiery, Joachim

doi:10.1161/01.atv.0000195791.83380.4c

Cited by 53 publications

(36 citation statements)

References 33 publications

(34 reference statements)

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“…In a study done to identify new genes of atherosclerosis susceptibility in macrophages from the two strains of rabbits with genetically determined high-atherosclerotic response (HAR) and low-atherosclerotic response (LAR), it was found that high expression of arginase I in macrophages may contribute to atherosclerosis resistance of LAR rabbits, possibly by conferring anti-inflammatory effects in the vessel wall. 521 This observation goes well with an earlier study where it was shown that arginase-1 was one of the 11 downregulated genes in macrophage foam cells. 223 In a study done to investigate the associations of the MnSOD polymorphism (valine-to-alanine) with its activity in leukocytes, macrophage apoptosis induced by Ox-LDL and CAD, it was found that the alanine allele in the signal peptide of MnSOD increases its mitochondrial activity and protects macrophages against the Ox-LDL-induced apoptosis, thereby reducing the risk of CAD.…”

Section: M a C R O P H A G E S A N D P O L Y M O R P H I S Msupporting

confidence: 88%

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Tiwari

Singh

Barthwal

2007

Medicinal Research Reviews

139

120

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Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acylCoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets. ß 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 4, 483-544, 2008

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Section: M a C R O P H A G E S A N D P O L Y M O R P H I S Msupporting

confidence: 88%

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Tiwari

Singh

Barthwal

2007

Medicinal Research Reviews

139

120

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“…20 Although Arg I could be a new candidate gene of atherosclerosis resistance, 21 no reports exist of the effects of Arg I in these diseases. As well, the fundamental mechanism still remains unexplored.…”

Section: Discussionmentioning

confidence: 99%

Arginase I Attenuates Inflammatory Cytokine Secretion Induced by Lipopolysaccharide in Vascular Smooth Muscle Cells

Wang

Chen²,

Qin³

et al. 2011

ATVB

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Objective-Inflammation plays an important role in atherosclerosis. Arginase I (Arg I) promotes the proliferation of vascular smooth muscle cells; however, the effect of Arg I on inflammation remains unknown. The present study investigated the role of Arg I in inflammation in vitro and in vivo. Methods and Results-Quantitative reverse transcription-polymerase chain reaction and Western blot analysis demonstrated that Arg I inhibited tumor necrosis factor-␣ production induced by lipopolysaccharide in human aortic smooth muscle cells. Inducible nitric oxide synthase substrate competition and nuclear factor-B activation were main contributors to lipopolysaccharide-mediated inflammatory cytokine generation. However, Arg I could attenuate the function of inducible nitric oxide synthase and inhibit the subsequent nuclear factor-B activation, leading to inhibition of tumor necrosis factor-␣ generation. Furthermore, upregulation of Arg I significantly decreased macrophage infiltration and inflammation in atherosclerotic plaque of rabbits, whereas downregulation of Arg I aggravated these adverse effects. Conclusion-The

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“…Arg1 variant with increased activity in cholesterol-fed rabbits 241% Arg1 (arginase 1) variant in atherosclerosis resistant rabbits was shown to have greater activity (1775,1785). Arg1 is greatly increased in regressing plaques and produces polyamines which promote resolution of inflammation and reduces iNOS production of NO in macrophages.…”

Section: Arg1mentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

379

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Identification of Macrophage Arginase I as a New Candidate Gene of Atherosclerosis Resistance

Cited by 53 publications

References 33 publications

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Arginase I Attenuates Inflammatory Cytokine Secretion Induced by Lipopolysaccharide in Vascular Smooth Muscle Cells

Molecular Biology of Atherosclerosis

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