Exacerbated transplant arteriosclerosis in inducible nitric oxide-deficient mice.
BACKGROUND
Inducible NO synthase (NOS2, or iNOS) is upregulated in grafts with transplant arteriosclerosis. However, the functional role of NOS2 in the pathogenesis of transplant arteriosclerosis remains unclear. NOS2 may regulate lesion development by modulating the early alloimmune response and/or late myointimal thickening.


RESULTS
To 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 significantly increased luminal occlusion (77.11+/-9.4% versus 40.8+/-13.6%, P<.0001) and intima/media ratios in allografts from NOS2 -/- recipients (1.9+/-1.3 versus 0.4+/-0.3, P=.0002). To elucidate potential mechanisms, we studied NOS2 effects on T-cell differentiation (Th1/Th2) and neointimal smooth muscle cell accumulation. Normalized mRNA levels for Th1- (signal transducer and activator of transcription [STAT] 4, interleukin [IL]-2, interferon-gamma) and Th2- (STAT 6, IL-4, and IL-5) associated factors were comparable in both groups. In contrast, quantitative analysis of the alpha-actin-positive area showed a significant increase in the contribution of smooth muscle cells within the neointima in allografts from NOS2 -/- recipients (28.2+/-2.0%) compared with wild-type controls (13.2+/-2.3%; P<.0001).


CONCLUSIONS
NOS2 plays a protective role in the development of transplant arteriosclerosis, suppressing neointimal smooth muscle cell accumulation.
Koglin
J
J
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Mass 02115, USA.
Glysing-Jensen
T
T
Mudgett
J S
JS
Russell
M E
ME
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology*; D002454:Cell Differentiation; D016027:Heart Transplantation / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D013601:T-Lymphocytes / Q000502:physiology; D014184:Transplantation, Homologous
D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse