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(Circulation. 2007;116:506-514.)
© 2007 American Heart Association, Inc.

Heart Failure

Disruption of Nitric Oxide Synthase 3 Protects Against the Cardiac Injury, Dysfunction, and Mortality Induced by Doxorubicin

Tomas G. Neilan, MD; Sarah L. Blake, MD; Fumito Ichinose, MD; Michael J. Raher, BSc; Emmanuel S. Buys, PhD; Davinder S. Jassal, MD; Elissa Furutani, BSc; Teresa Miriam Perez-Sanz, MD; Amanda Graveline, BSc; Stefan P. Janssens, MD, PhD; Michael H. Picard, MD; Marielle Scherrer-Crosbie, MD, PhD; Kenneth D. Bloch, MD

From the Cardiovascular Research Center (T.G.N., S.L.B., F.I., M.J.R., E.S.B., E.F., A.G., K.D.B.) and Cardiac Ultrasound Laboratory (T.G.N., D.S.J., T.M.P.-S., M.H.P., M.S.-C.) in the Cardiology Division of the Department of Medicine, and Department of Anesthesia and Critical Care (F.I., K.D.B.), Massachusetts General Hospital, Charlestown; and Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Cardiology Division, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium (S.P.J.).

Correspondence to Tomas G. Neilan, MD, Cardiac Ultrasound Laboratory, Division of Cardiology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. E-mail tneilan{at}partners.org

Received July 17, 2006; accepted May 11, 2007.

Background— Flavoprotein reductases are involved in the generation of reactive oxygen species by doxorubicin. The objective of the present study was to determine whether or not one flavoprotein reductase, endothelial nitric oxide synthase (nitric oxide synthase 3 [NOS3]), contributes to the cardiac dysfunction and injury seen after the administration of doxorubicin.

Methods and Results— A single dose of doxorubicin (20 mg/kg) was administered to wild-type (WT) mice, NOS3-deficient mice (NOS3^–/–), and mice with cardiomyocyte-specific overexpression of NOS3 (NOS3-TG). Cardiac function was assessed after 5 days with the use of echocardiography. Doxorubicin decreased left ventricular fractional shortening from 57±2% to 47±1% (P<0.001) in WT mice. Compared with WT mice, fractional shortening was greater in NOS3^–/– and less in NOS3-TG after doxorubicin (55±1% and 35±2%; P<0.001 for both). Cardiac tissue was harvested from additional mice at 24 hours after doxorubicin administration for measurement of cell death and reactive oxygen species production. Doxorubicin induced cardiac cell death and reactive oxygen species production in WT mice, effects that were attenuated in NOS3^–/– and were more marked in NOS3-TG mice. Finally, WT and NOS3^–/– mice were treated with a lower dose of doxorubicin (4 mg/kg) administered weekly over 5 weeks. Sixteen weeks after beginning doxorubicin treatment, fractional shortening was greater in NOS3^–/– than in WT mice (45±2% versus 28±1%; P<0.001), and mortality was reduced (7% versus 60%; P<0.001).

Conclusions— These findings implicate NOS3 as a key mediator in the development of left ventricular dysfunction after administration of doxorubicin.

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