期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 34, 期 9, 页码 2001-2011出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.113.303145
关键词
inflammasomes; interleukins
资金
- National Science Foundation of China [81230006, 81000069, 81000090]
- Chinese Ministry of Science and Technology [2012CB945104]
- National Science Foundation of Beijing [7132043, 7142050]
Objective-Interleukin (IL)-1 beta and IL-18 are key proinflammatory cytokines that play important roles in the pathophysiology of vein graft remodeling. However, the mechanism of IL-1 beta/IL-18 production and its role in the development of graft remodeling remain unclear. Approach and Results-IL-1 beta/IL-18 were rapidly expressed in venous interposition grafts. Vascular smooth muscle cell (VSMC) death and monocytic inflammasome activation occurred in grafted veins. Necrotic VSMCs induced the expression of IL-1 beta, IL-18, and other inflammasome-associated proteins in monocytes, which was partially inhibited by their antagonist, recombinant IL-1ra-Fc-IL-18bp. Activated monocytes stimulated proliferation of VSMCs by activating cell growth-related signaling molecules (AKT, STAT3, ERK1/2, and mTOR [AKT/protein kinase B, signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, mammalian target of rapamycin]) and increasing production of platelet-derived growth factor-bb; these effects were suppressed by IL-1ra-Fc-IL-18bp. Activated monocytes also promoted migration of VSMCs, which was independent of IL-1 beta/IL-18 signaling. Importantly, administration of IL-1ra-Fc-IL-18bp inhibited activation of cell growth-related signaling molecules, VSMC proliferation, and vein graft thickening in vivo. Conclusions-Our work identified an interaction among necrotic VSMCs, monocytes, and viable VSMCs through IL-1 beta/IL-18 signaling, which might be exploited as a therapeutic target in vein graft remodeling.
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