Effects of selective inhibitors of nitric oxide synthase-2 dimerization on acute cardiac allograft rejection.
BACKGROUND
Nitric oxide synthase-2 (NOS2) is expressed during acute cardiac allograft rejection in association with myocardial inflammation, contractile dysfunction, and death of cardiomyocytes by necrosis and apoptosis. Recently, allosteric inhibitors of NOS2 monomer dimerization that block NOS2 activity have been developed.


RESULTS
To investigate effects of selective NOS2 blockade, 15 mg/kg of BBS-1 or BBS-2 was administered twice daily subcutaneously to rats starting the day of heterotopic heart transplantation. Cardiac allograft survival was increased significantly, from 6.8 days in controls to 13.3 and to 14.2 days in NOS2-inhibited allografts. At day 5 after heart transplantation, synthesis of NOx was reduced by 53%. There were significantly fewer T lymphocytes and macrophages in the inflammatory infiltrate, as well as less edema and cardiomyocyte damage, and the International Society of Heart and Lung Transplantation score fell from 5 to 4 and 3.5. NOS2 and nitrotyrosine immunostaining and the mean numbers of apoptotic cells and of apoptotic cardiomyocytes were significantly diminished in the treated allografts.


CONCLUSIONS
The data indicate that selective inhibition of NOS2 dimerization prolongs survival and reduces myocardial inflammation and cardiomyocyte damage in acute cardiac allograft rejection.
Szabolcs
Matthias J
MJ
Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Sun
Ji
J
Ma
Ningsheng
N
Albala
Arline
A
Sciacca
Robert R
RR
Philips
Gary B
GB
Parkinson
John
J
Edwards
Niloo
N
Cannon
Paul J
PJ
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007279:Injections, Subcutaneous; D008264:Macrophages / Q000473:pathology; D008297:Male; D009205:Myocarditis / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D013601:T-Lymphocytes / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology*; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D007093:Imidazoles; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat