Details

Autor(en) / Beteiligte

• Shahid, Mohd
• Wen, Shuguang
• Shelton, Georgia
• Buswell, Mary D
• OʼRourke, Caitlin
• Barnes, Hanna
• Newaz, Mohammad
• Malhotra, Rajeev
• Wu, Mei X

Titel

Abstract 11502: Immediately Early Response Gene X-1 Paucity Inhibits Atherosclerosis in Apolipoprotein E Deficient Mice

Ist Teil von

• Circulation (New York, N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A11502-A11502

Ort / Verlag

by the American College of Cardiology Foundation and the American Heart Association, Inc

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• IntroductionEmerging evidence suggests that both the numbers and phenotype of macrophages play a crucial role in the development of atherosclerosis. Classically activated macrophages (CAMs) are enriched in progressing plaques and differentiate into foam cells, whereas alternatively activated macrophages (AAMs) are abundant in regressing plaques and inhibit inflammation. Immediately early response gene x-1 (IEX-1) is a stress inducible gene that is highly expressed in macrophages and regulates their phenotype. We hypothesize that IEX-1 is required for atherogenesis by regulating macrophage phenotype.Methods and ResultsWe generated IEX-1-deficient (IEX-1) mice on an apolipoprotein E knockout (ApoE) background. We fed these mice a normal chow for 20 weeks and assessed atherosclerotic burden. Aortic calcification and macrophage burden in the aortic arch were markedly reduced in ApoEIEX-1 (10±0.8 and 5±0.3 AU) as compared to ApoE littermates (27±2.8 and 9±0.5 AU, p<0.001 for both, n=8). Oil-Red-O staining of aortic sinus sections showed multiple atherosclerotic lesions in ApoE mice, that was dramatically reduced in ApoEIEX-1 mice (67±7 vs. 19±7 mm, p=0.001). IEX-1 deficiency did not alter body weight, plasma cholesterol, or triglyceride levels. Flow cytometric analysis of single cell suspension of whole aorta revealed that the percentage of CAMs (F4/80+CD11C+) decreased by ~50% (13±2 vs. 26±2%, p=0.01, n=4), concomitant with an increase in AAMs (F4/80+CD206+) by 2-fold (19±2 vs. 9±1%, p=0.01) in ApoEIEX-1 as compared to ApoE mice. Consistently, the mRNA levels of inflammatory cytokines iNOS, IL-1β, and CD11c in aorta but not in liver were markedly reduced in ApoEIEX-1 mice compared to ApoE animals. Furthermore, cultured bone marrow-derived macrophages with IEX-1 deficiency exhibited reduced CAM polarization and pro-inflammatory cytokine expression induced by interferon-γ compared to wild-type (WT) cells.ConclusionIEX-1 deficiency inhibits atherosclerosis in ApoE mice by favoring the AAM over CAM phenotype of aortic macrophages in a cell-autonomous manner, thereby inhibiting CAM-induced inflammation.