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• W2518097921 abstract "In Brief Background Inflammation is central to the pathogenesis of transplant arteriosclerosis (TA). We questioned whether physiologic levels of anti-inflammatory A20 influence TA severity. Methods We performed major histocompatibility complex mismatched aorta to carotid artery interposition grafts, using wild type (WT) or A20 heterozygote (HET) C57BL/6 (H-2b) donors and BALB/c (H-2d) recipients, and conversely BALB/c donors and WT/HET recipients. We analyzed aortic allografts by histology, immunohistochemistry, immunofluorescence, and gene profiling (quantitative real-time reverse-transcriptase polymerase chain reaction). We validated select in vivo A20 targets in human and mouse smooth muscle cell (SMC) cultures. Results We noted significantly greater intimal hyperplasia in HET versus WT allografts, indicating aggravated TA. Inadequate upregulation of A20 in HET allografts after transplantation was associated with excessive NF-кB activation, gauged by higher levels of IkBα, p65, VCAM-1, ICAM-1, CXCL10, CCL2, TNF, and IL-6 (mostly localized to SMC). Correspondingly, cytokine-induced upregulation of TNF and IL-6 in human and mouse SMC cultures inversely correlated with A20 expression. Aggravated TA in HET versus WT allografts correlated with increased intimal SMC proliferation, and a higher number of infiltrating IFNγ+ and Granzyme B+ CD4+ T cells and natural killer cells, and lower number of FoxP3+ regulatory T cells. A20 haploinsufficiency in allograft recipients did not influence TA. Conclusions A20 haploinsufficiency in vascular allografts aggravates lesions of TA by exacerbating inflammation, SMC proliferation, and infiltration of pathogenic T cells. A20 single nucleotide polymorphisms associating with lower A20 expression or function in donors of vascularized allografts may inform risk and severity of TA, highlighting the clinical implications of our findings. Moll et al report that ubiquitin-editing protein A20 haploinsufficiency in vascular allografts aggravates transplant atheriosclerosis in a C57BL/6 aorta to BALB/c carotid artery interposition transplant model, by exacerbating inflammation, smooth muscle cell proliferation and the infiltration of pathogenic T cells." @default.
• W2518097921 created "2016-09-16" @default.
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• W2518097921 date "2016-11-01" @default.
• W2518097921 modified "2023-10-12" @default.
• W2518097921 title "A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts" @default.
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• W2518097921 doi "https://doi.org/10.1097/tp.0000000000001407" @default.
• W2518097921 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5077649" @default.
• W2518097921 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27495763" @default.
• W2518097921 hasPublicationYear "2016" @default.
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