(Circulation. 1999;99:836-842.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Attenuated Acute Cardiac Rejection in NOS2 -/- Recipients Correlates With Reduced Apoptosis
From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., M.E.R.), Brigham and Women's Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston, Mass; Cardiovascular Research Laboratories, Department of Pathology and Laboratory Medicine, St Paul's Hospital, University of British Columbia (D.J.G., C.M.C., B.M.M.), and QLT Phototherapeutics Inc (D.J.G., C.M.C.), Vancouver, British Colombia, Canada; and Merck Research Laboratories (J.S.M.), Rahway, NJ.
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—The mechanisms through which NOS2-mediated pathways regulate graft failure in acute cardiac rejection are ill defined. To determine whether apoptosis promoted by NOS2 may contribute, we used a heterotopic transplant model to study mouse cardiac allografts placed in recipients with targeted gene deletion of NOS2.
Methods and Results—Using 5 different indexes of
apoptosis, we showed that mouse cardiac allografts placed in
NOS2 -/- recipients (n=7) had reduced apoptotic activity
compared with those in NOS2 +/+ controls (n=8). There were
significantly fewer TUNEL-positive nuclei per high-powered field
(P<0.01), less DNA fragmentation (antinucleosome ELISA;
P<0.05), lower corrected transcript levels for
caspase-1 and -3 (32P reverse transcriptase–polymerase
chain reaction; P<0.01), and reduced caspase-3 activity
(cleavage of DEVD-pNA [P<0.001] and poly
[ADP-ribose] polymerase) in grafts from NOS2 -/- recipients. This
concordant reduction in apoptotic indexes paralleled the
improved histological outcome of grafts transplanted
into NOS2 -/- recipients (assessed as rejection scores;
P=0.012). To identify pathways controlled by NOS2, we
compared intragraft transcript levels of potential triggers and
regulators. Whereas Fas ligand/Fas and tumor necrosis factor
(TNF)-
/TNF receptor-1 levels were not altered by NOS2 deficiency,
transcript levels for p53 were significantly lower in grafts from NOS2
-/- recipients, coinciding with a significant increase in the
antiapoptotic Bcl-2/Bax balance and decrease in
Bcl-Xl levels.
Conclusions—Using NOS2 knockout mice, we demonstrated that NOS2-mediated pathways can promote acute rejection, at least in part, by inducing apoptotic cell death. When NOS2 is present, p53 might control NOS2-mediated apoptosis by stimulating Bax and repressing Bcl-2 and Bcl-Xl expression, which may activate the cell death program in the rejecting heart.
Key Words: transplantation • immune system • genes
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