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(Circulation. 2001;103:2514.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Acute Cardiac Allograft Rejection in Nitric Oxide Synthase-2^-/- and Nitric Oxide Synthase-2^+/+ Mice

Effects of Cellular Chimeras on Myocardial Inflammation and Cardiomyocyte Damage and Apoptosis

Matthias J. Szabolcs, MD; Ninsheng Ma, MD; Eleni Athan, PhD; Jing Zhong, MD; Ming Ming, MD; Robert R. Sciacca, EngScD; Jens Husemann, MD; Arline Albala, MA; Paul J. Cannon, MD

From the Departments of Medicine (R.R.S., A.A., P.J.C.), Physiology (J.H.), Pathology (M.J.S., E.A., J.Z., M.M.), and Surgery (N.M.), Columbia University College of Physicians and Surgeons, New York, NY.

Correspondence to Paul J. Cannon, MD, Department of Medicine, Division of Cardiology, Columbia University, 630 W 168th St, New York, NY 10032. E-mail pjc4{at}columbia.edu

Background—The contribution of nitric oxide synthase (NOS)-2 to myocardial inflammation and cardiomyocyte necrosis and apoptosis during allograft rejection was investigated through heterotopic cardiac transplantation in mice.

Methods and Results—In the first experiments, hearts from C3H donor mice were transplanted into NOS-2^-/- and NOS-2^+/+ C57BL/6J.129J recipients. A second series of experiments included NOS-2^-/- donor hearts transplanted into NOS-2^-/- recipients and wild-type NOS-2^+/+ donor hearts transplanted into wild-type NOS-2^+/+ recipients. (All donors were C57BL/6J and recipients were C57BL/6J.129J.) In the first series of experiments, no significant differences were observed in allograft survival, rejection score, total number of apoptotic nuclei (TUNEL), total number of apoptotic cardiomyocytes, or graft NOS-2 mRNA and protein. Positive NOS-2 immunostaining occurred in endothelial cells and cardiomyocytes in the allografts; the inflammatory infiltrate was NOS-2 positive only when recipients were NOS-2^+/+. In the second series of experiments, cardiac allograft survival was significantly increased in the NOS-2^-/- mice (26±13 versus 17±8 days, P<0.05), along with significant reductions in inflammatory infiltrate, rejection score, and total number of apoptotic nuclei (23.5±9.5 versus 56.4±15.3, P<0.01) and of apoptotic cardiomyocytes (2.9±1.6 versus 6.9±2.7, P<0.05). No NOS-2 or nitrotyrosine, a marker of peroxynitrite exposure, was detected in NOS-2^-/- allografts transplanted into NOS-2^-/- recipients.

Conclusions—The data suggest that NO derived from NOS-2 contributes to the inflammatory response and to cardiomyocyte damage and apoptosis during acute cardiac allograft rejection.

Key Words: apoptosis • rejection • nitric oxide synthase • transplantation

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