Abstract 540: Loss of Function Studies Highlight the Vasculoprotective Effect of A20 in Transplant Arteriosclerosis
Abstract only Transplant arteriosclerosis (TA) is an accelerated form of atherosclerosis largely driven by the immune response to the allograft. As for all atherosclerotic disease, inflammation is central to vascular remodeling associated with TA. We have shown that overexpression of the NF-κB inhib...
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| Published in: | Arteriosclerosis, thrombosis, and vascular biology Vol. 33; no. suppl_1 |
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| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
01-05-2013
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| Online Access: | Get full text |
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| Summary: | Abstract only Transplant arteriosclerosis (TA) is an accelerated form of atherosclerosis largely driven by the immune response to the allograft. As for all atherosclerotic disease, inflammation is central to vascular remodeling associated with TA. We have shown that overexpression of the NF-κB inhibitory protein in totally mismatched (C57BL/6 to BALB/c) aortic to carotid vascular allografts protects from TA. A20 inhibits TA thanks to its anti-inflammatory and anti-apoptotic functions in endothelial cells (EC), anti-inflammatory and anti-proliferative functions in smooth muscles cells (SMC), pro-apoptotic function in neointimal SMC, and to favoring regulatory FOXP3+ over pathogenic Th1/Th17 T cells. In this work, we analyzed the impact of A20 knockdown on TA by using aortic allografts from A20 heterozygous (A20-+/- HET) mice. Partial loss of A20 in aortic allografts caused significantly greater TA lesions, measured by intima over media ratios (I/M 1.79±0.18 in HET vs. 1.04±0.17 in wild type (WT) allografts; p<0.01). This was associated with higher inflammation as evaluated by VCAM-1 immunostaining and granulocyte infiltration, lower expression of the anti-inflammatory and tolerogenic cytokine IL-10, and greater incidence of thrombosis (3/11 vs. 0/10) in HET vs. WT allografts. These results are particularly relevant to newly discovered A20 single nucleotide polymorphisms (SNPs) that are less effective in inhibiting inflammation, and have been associated with increased risk of coronary artery disease in diabetic patients. Based on these results, we conclude that A20 plays an important physiologic role in the vascular remodeling of TA. We propose that tailored A20-based vascular therapies could decrease incidence and severity of TA, and synergize with or minimize use of immunosuppression in solid organ transplantation. |
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| ISSN: | 1079-5642 1524-4636 |
| DOI: | 10.1161/atvb.33.suppl_1.A540 |