Nitric oxide (NO) has been shown to play a key role in the regulation of
cardiac hypertrophy and
fibrosis in response to
myocardial ischemia in part by antagonizing the action of
angiotensin II (Ang II). In this study, we investigated the potential protective role of human
endothelial nitric oxide synthase (eNOS) in left ventricular (LV) remodeling after
myocardial infarction (MI) by a somatic gene transfer approach. Male Wistar rats underwent coronary artery
ligation to induce MI. One week after surgery, adenovirus encoding the human eNOS or
luciferase gene under the control of the CMV promoter/enhancer was injected into rats via the tail vein, and animals were sacrificed at 1 and 5 weeks after gene transfer. Successful gene transfer was evaluated based on increased levels of NO and cGMP in the heart, measured at one week after eNOS gene delivery. Six weeks after MI, the LV end-diastolic pressure, heart weight, LV axis length and cardiomyocyte size were markedly increased compared to the
Sham group, while eNOS gene delivery significantly reduced these parameters. Rats receiving control virus developed considerably more fibrotic lesions identified by Sirius Red staining and
collagen I immunostaining compared to
Sham rats, and eNOS gene delivery significantly reduced
collagen accumulation. eNOS gene transfer also reduced TUNEL-positive apoptotic cells. The cardioprotective effect of NO was accompanied by reduced
NADH and
NADPH oxidase activities and
superoxide formation,
TGF-beta1 and p27 levels, JNK activation,
NF-kappa B nuclear translocation, and
caspase-3 activity. This study shows that NO may play an important role in attenuating cardiac remodeling and apoptosis after
myocardial infarction via suppression of oxidative stress-mediated signaling pathways.