From the Cardiovascular Biology Laboratory, Harvard School of Public
Health (J.K., T.G.-J., M.E.R.), Cardiovascular Medicine Division, Brigham and
Women's Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston,
Mass, and Merck Research Laboratories, Rahway, NJ (J.S.M.).
Correspondence to Mary E. Russell, MD, Cardiovascular Biology Laboratory, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115. E-mail russell{at}cvlab.harvard.edu
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.
Methods and 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
(77.1±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-
Conclusions—NOS2 plays a protective role in the development of
transplant arteriosclerosis, suppressing
neointimal smooth muscle cell accumulation.
© 1998 American Heart Association, Inc.
Basic Science Reports
Exacerbated Transplant Arteriosclerosis in Inducible Nitric Oxide–Deficient Mice
) and Th2- (STAT 6,
IL-4, and IL-5) associated factors were comparable in both groups. In
contrast, quantitative analysis of the 
-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).
Key Words: transplantation • immunology • lymphocytes • remodeling • muscle, smooth
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