Effects of AGI-1096, a novel antioxidant compound with anti-inflammatory and antiproliferative properties, on rodent allograft arteriosclerosis

Seiichiro Murata, Cynthia L. Sundell, Maarten A. Lijkwan, Leora B. Balsam, Pekka Hammainen, Caroline Coleman, Chris York, Jayraz Luchoomun, Ki Ling Suen, Randy Howard, Patricia K. Somers, Randall E. Morris, Robert C. Robbins

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background. AGI-1096 is a novel phenolic intracellular antioxidant with anti-inflammatory and antiproliferative properties. In vitro, AGI-1096 inhibited the inducible expression of vascular cell adhesion molecule (VCAM)-1, E-selectin, and monocyte Chemoattractant protein (MCP)-1 in endothelial cells and tumor necrosis factor (TNF)-α and interleukin (IL)-1β secretion from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells. It also inhibited serum-stimulated proliferation of aortic smooth-muscle cells. In vivo, AGI-1096 demonstrated anti-inflammatory properties in a murine delayed-type hypersensitivity model. Given these antioxidant, anti-inflammatory and antiproliferative properties, we reasoned that AGI-1096 may be able to prevent chronic allograft arteriosclerosis. This hypothesis was tested in a rodent aortic transplantation model. Methods. Donor descending aortas from August-Copenhagen-Irish rats were heterotopically transplanted/into Lewis rat abdomens in end-to-end fashion. Animals were assigned to six groups as follows: AGI-1096 0 mg/kg per day (vehicle, n=10), 10 mg/kg per day (n=10), 20 mg/kg per day (n=10), 40 mg/kg per day (n=10), positive control (cyclosporine A 10 mg/kg per day by oral gavage, n=10), and isograft negative control (Lewis-to-Lewis, n=5). AGI-1096 was administrated subcutaneously to recipient animal three days before the surgery and for 90 days thereafter. On day 90, the paraffin-embedded allograft sections were stained with Elastin-van Gieson's stain, and the intima/media (I/M) ratio and luminal narrowing (%LN) was assessed by digital morphometry. Results. AGI-1096 demonstrated dose-dependent lowering of the I/M ratio and %LN when compared with vehicle controls. Conclusion. This is the first study to show that treatment of allograft recipients with AGI-1096 decreases the incidence of transplant arteriosclerosis. These data suggest that AGI-1096 may be a promising new therapeutic agent for use in clinical transplantation.

Original languageEnglish (US)
Pages (from-to)1494-1500
Number of pages7
Issue number10
StatePublished - May 27 2004
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation


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