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Home > Vascular Annual Meeting > siracuse_A20_protects

A20 Protects Against Accelerated Atherosclerosis in Aortic Allografts

Jeffrey J. Siracuse, Mark D. Fisher, Scott M. Damrauer, Lynn Y. Choi, Cleide G. Da Silva, Eva Csizmadia, Elizabeth R. Maccariello, Soizic Daniel, Christiane Ferran.
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass.

OBJECTIVES: A20 is part of the regulatory atheroprotective response of endothelial (EC) and smooth muscle (SMC) cells to injury. It is a NF-kB dependent gene with potent anti-inflammatory effects in EC and SMC, through blockade of NF-kB. A20 also serves an anti-proliferative function in SMC and opposite anti-apoptotic or pro-apoptotic functions in EC and neointimal SMC. Based on these functions, A20 would be a good candidate to prevent accelerated arteriosclerosis in an aortic allograft transplant model. This is supported by A20 expression in EC and SMC correlating with the absence of atherosclerosis in rat kidney allografts and long-term functioning human kidney allografts

METHODS: Fully mismatched C57BL/6 (H2b) and BALB/c (H2d), were used as donors and recipients of an aortic to carotid allograft. In this combination, atheroclerotic lesions start at 4 weeks and become occlusive by 8 weeks when left without immunosuppression. A20 expression in the graft was achieved by recombinant adenoviral (rAd) mediated gene transfer prior to retrieval. Control mice were infused with saline or control rAd beta-galactosidase. The grafts were harvested at 4 weeks and analyzed for lesions by measuring intima to media ratios (I/M) and by immunohistochemistry for markers of inflammation and of the immune response.

RESULTS: A20 expressing vessels were significantly protected from intimal hyperplasia with I/M reaching 0.4±0.09 as compared to saline (1.62±0.17) and beta-Gal (1.86±0.06) treated vessels. This effect of A20 did not associate with a decrease in infiltrating CD3, CD4 or CD8 T cells in A20 vessels as compared to controls. A possible modification of the phenotype of these T cells (T-regs vs. effector T cells) is being explored. Rather, protection from atherosclerosis correlated with increased expression of endothelial and inducible nitric oxide synthases (NOS) in EC and SMC of A20 expressing vessels, suggesting that this effect was, at least in part, related to increased in situ production of nitric oxide.

CONCLUSIONS: This is the first direct evidence that expression in the vessel wall of the anti-inflammatory and atheroprotective protein A20 prevents accelerated arteriosclerosis in the transplant model through a mechanism implicating increased expression of NOS.

AUTHOR DISCLOSURES: J.J. Siracuse, None; M.D. Fisher, None; S.M. Damrauer, None; L.Y. Choi, None; C.G. Da Silva, None; E. Csizmadia, None; E.R. Maccariello, None; S. Daniel, None; C. Ferran, None.