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• W2775694593 abstract "Transplant arteriosclerosis (TA) is largely driven by the immune response to the allograft. As for a number of vascular pathologies, inflammation including activation of the IFNγ/STAT1 axis is central to vascular remodeling associated with TA. Strategies to interrupt IFNγ-mediated JAK-STAT signaling in the vasculature are hence particularly attractive. In this study, we investigated the impact of the NF-κB inhibitory protein A20 on IFNγ signaling in the vasculature. For mechanistic analysis of A20’s effect on IFNγ driven vascular remodeling, we performed in vitro A20 loss and gain of function studies using human coronary artery EC and SMC. Subsequently, we evaluated the impact of partial loss of A20 on TA using a totally mismatched (C57BL/6 to BALB/c) aortic to carotid vascular transplants, where allografts from A20 +/- were compared to those from WT mice. Silencing of A20 in vitro in EC and SMC led to a significant super-induction of bona fide IFNγ dependent genes including atherogenic genes namely the adhesion molecule ICAM1, the chemokines MCP1, IP10 and I-TAC, the transcription factor IRF1 and the metabolic enzyme IDO. In contrast, overexpression of A20 in SMC significantly decreased all IFNγ-dependent genes. We elucidated that A20 impacted IFNγ signaling by controlling availability of the key IFNγ signal mediator STAT1. A20 silencing increased while A20 over-expression decreased STAT1 levels. Further, we demonstrated that A20 regulated STAT1 expression independent of its NF-κB inhibitory function but by affecting basal subthreshold levels of its upstream inducer, IFNβ. In vivo, these findings translated into a significant aggravation of TA lesions in A20 HET versus WT allografts, as evaluated by intima over media ratios. Altogether, these data uncover for the first time an important physiologic role for A20 as a regulator of pathologic vascular remodeling of TA, in part thanks to its novel inhibitory effect on IFNγ signaling in vascular cells. These results are clinically relevant in light of A20 SNPs associated with decreased expression and function. Therapeutically, our data strongly suggest that A20-based vascular therapies could decrease incidence and severity of TA, and minimize use of immunosuppression in vascularized organ transplantation." @default.
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• W2775694593 date "2014-07-01" @default.
• W2775694593 modified "2023-09-26" @default.
• W2775694593 title "Partial Loss of A20 Aggravates Transplant Arteriosclerosis through De-Regulation of IFNβ/STAT1 Axis, Thereby Enhancing Pathologic IFNγ Signaling." @default.
• W2775694593 doi "https://doi.org/10.1097/00007890-201407151-00066" @default.
• W2775694593 hasPublicationYear "2014" @default.
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