EXACERBATED TRANSPLANT ARTERIOSCLEROSIS IN INDUCIBLE NITRIC OXIDE-DEFICIENT MICE

Background-Inducible NO synthase (NOS2, or iNOS) is upregulated in gra fts with transplant arteriosclerosis. However, the functional role of NOS2 in the pathogenesis of transplant arteriosclerosis remains unclea r. NOS2 may regulate lesion development by modulating the early alloim mune response and/or late myointimal thickening. Methods and Results-T o determine whether NOS2-mediated pathways protect against or promote transplant arteriosclerosis, we used NOS2-deficient mice as recipients in our vascularized chronic cardiac rejection model. The severity of vascular thickening in 55-day grafts placed into NOS2 -/- recipients ( n=13) was compared with that in wild-type recipients (n=15). Computer- assisted analysis of all elastin-stained vessels (n=283) showed signif icantly increased luminal occlusion (77.1+/-9.4% versus 40.8+/-13.6%, P<.0001) and intima/media ratios in allografts from NOS2 -/- recipient s (1.9+/-1.3 versus 0.4+/-0.3, P=.0002), To elucidate potential mechan isms, we studied NOS2 effects on T-cell differentiation (Th-1/Th-2) an d neointimal smooth muscle cell accumulation. Normalized mRNA levels f or Th-1-(signal transducer and activator of transcription [STAT] 4, in terleukin [IL]-2, interferon-gamma) and Th-2- (STAT 6, IL-4, and IL-5) associated factors were comparable in both groups. In contrast? quant itative analysis of the alpha-actin-positive area showed a significant increase in the contribution of smooth muscle cells within the neoint ima in allografts from NOS2 -/- recipients (28.2+/-2.0%) compared with wild-type controls (13.2+/-2.3%; P<.0001), Conclusions-NOS2 plays a p rotective role in the development of transplant arteriosclerosis, supp ressing neointimal smooth muscle cell accumulation.