Identification of a Non-Growth Factor Role for GM-CSF in Advanced Atherosclerosis. Issue 2 (16th January 2015)

• Record Type: Journal Article
• Authors: Subramanian, Manikandan; Thorp, Edward; Tabas, Ira
• Is Part Of: Circulation research. Volume 116:Issue 2(2015)
• Publication Date: 2015-01-16
• Subjects: Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.116.304794
• Languages: English
• ISSNs: 0009-7330

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title> <underline>Rationale:</underline> </title> <p>Granulocyte macrophage colony-stimulating factor (GM-CSF, Csf2) is a growth factor for myeloid-lineage cells that has been implicated in the pathogenesis of atherosclerosis and other chronic inflammatory diseases. However, the role of GM-CSF in advanced atherosclerotic plaque progression, the process that gives rise to clinically dangerous plaques, is unknown.</p> </sec> <sec> <title> <underline>Objective:</underline> </title> <p>To understand the role of GM-CSF in advanced atherosclerotic plaque progression.</p> </sec> <sec> <title> <underline>Methods and Results:</underline> </title> <p> <italic>Ldlr</italic> <sup>−/−</sup> mice and <italic>Csf2</italic><sup>−/−</sup><italic>Ldlr</italic><sup>−/−</sup> mice were fed a Western-type diet for 12 weeks, and then parameters of advanced plaque progression in the aortic root were quantified. Lesions from the GM-CSF–deficient mice showed a substantial decrease in 2 key hallmarks of advanced atherosclerosis, lesional macrophage apoptosis and plaque necrosis, which indicates that GM-CSF promotes plaque progression. Based on a combination of in vitro and in vivo studies, we show that the mechanism involves GM-CSF–mediated production of interleukin-23, which increases apoptosis susceptibility in macrophages by promoting proteasomal degradation of the cell survival protein Bcl-2 (B-cell lymphoma 2) and by increasing oxidative stress.</p> </sec> <sec> <title> <underline>Conclusions:</underline> </title> <p>In low-density lipoprotein–driven atherosclerosis in mice, GM-CSF promotes advanced plaque progression by increasing macrophage apoptosis susceptibility. This action of GM-CSF is mediated by its interleukin-23–inducing activity rather than its role as a growth factor.</p> </sec> </abstract>