Effects of AGI-1096, a novel antioxidant compound with anti-inflammatory and antiproliferative properties, on rodent allograft arteriosclerosis.
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)-alpha and interleukin (IL)-1beta 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 animals 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 (1%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.


CONCLUSIONS
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.
Murata
Seiichiro
S
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, CA 94305, USA.
Sundell
Cynthia L
CL
Lijkwan
Maarten A
MA
Balsam
Leora B
LB
Hammainen
Pekka
P
Coleman
Caroline
C
York
Chris
C
Luchoomun
Jayraz
J
Suen
Ki-Ling
KL
Howard
Randy
R
Somers
Patricia K
PK
Morris
Randall E
RE
Robbins
Robert C
RC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry; D001011:Aorta / Q000166:cytology / Q000473:pathology* / Q000637:transplantation*; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D002087:Butyrates / Q000008:administration & dosage* / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D010636:Phenols / Q000008:administration & dosage* / Q000737:chemistry; D011651:Pulmonary Artery / Q000166:cytology; D051381:Rats; D011919:Rats, Inbred Strains; D014184:Transplantation, Homologous
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002087:Butyrates; D016207:Cytokines; D018836:Inflammation Mediators; D010636:Phenols; C487958:elsibucol