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(Circulation. 2002;106:873.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Development of Heart Failure and Congenital Septal Defects in Mice Lacking Endothelial Nitric Oxide Synthase

Qingping Feng, MD, PhD; Wei Song, MD, PhD; Xiangru Lu, MD; Joel A. Hamilton, BSc; Ming Lei, MD; Tianqing Peng, MD; Siu-Pok Yee, PhD

From the Departments of Medicine, Physiology, Pharmacology, and Toxicology, Cardiology Research Laboratory, London Health Sciences Centre; and Departments of Oncology and Biochemistry, Cancer Research Laboratories, London Regional Cancer Center (S.-P.Y.), University of Western Ontario, London, Ontario, Canada.

Correspondence to Dr Qingping Feng, Department of Medicine, London Health Sciences Centre, Victoria Campus, 375 South St, London, Ontario, Canada N6A 4G5. E-mail qfeng{at}uwo.ca

Background— Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an important role in the regulation of cell growth, apoptosis, and tissue perfusion. Recent studies showed that mice deficient in eNOS developed abnormal aortic bicuspid valves. The aim of the present study was to additionally investigate the role of eNOS in heart development.

Methods and Results— We examined postnatal mortality, cardiac function, and septum defects in eNOS^-/-, eNOS^+/-, and wild-type mice. Postnatal mortality was significantly increased in eNOS^-/- (85.1%) and eNOS^+/- (38.3%) compared with wild-type mice (13.3%, P<0.001). Postmortem examination found severe pulmonary congestion with focal alveolar edema in mice deficient in eNOS. Heart shortening determined by ultrasound crystals was significantly decreased in eNOS^-/- compared with wild-type mice (P<0.05). Congenital atrial and ventricular septal defects were found in neonatal hearts. The incidence of atrial or ventricular septal defects was significantly increased in eNOS^-/- (75%) and eNOS^+/- (32.4%) neonates compared with those of the wild-type mice (4.9%). At embryonic days 12.5 and 15.5, cardiomyocyte apoptosis and myocardial caspase-3 activity were increased in the myocardium of eNOS^-/- compared with wild-type embryos (P<0.01), and increases in apoptosis persisted to neonatal stage in eNOS^-/- mice.

Conclusions— Deficiency in eNOS results in heart failure and congenital septal defects during cardiac development, which is associated with increases in cardiomyocyte apoptosis. Our data demonstrate that eNOS plays an important role in normal heart development.

Key Words: nitric oxide • heart failure • heart defects, congenital • heart septal defects • apoptosis

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