Inhibition of TGF-beta1 signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through angiogenesis and reduction of apoptosis.
BACKGROUND
Endothelial nitric oxide synthase and nitric oxide have been implicated in protection against myocardial ischemia injury. However, the angiogenic effect of endothelial nitric oxide synthase on infarcted myocardium and the role of tumor growth factor beta1 signaling in cardiac remodeling mediated by endothelial nitric oxide synthase/nitric oxide have not yet been elucidated.


METHODS
Human endothelial nitric oxide synthase gene in an adenovirus vector was delivered locally into rat heart 4 days prior to the induction of myocardial infarction by left anterior descending coronary artery ligation. Cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and neovascularization was identified immunohistochemically.


RESULTS
Endothelial nitric oxide synthase gene transfer significantly reduced infarct size and improved cardiac contractility and left ventricular diastolic function at 24 h after myocardial infarction. In addition, endothelial nitric oxide synthase significantly reduced myocardial-infarction-induced cardiomyocyte apoptosis. Activation of tumor growth factor beta1 and Smad-2 after myocardial infarction was also dramatically reduced by endothelial nitric oxide synthase. Moreover, the deterioration of both systolic and diastolic functions, in conjunction with thin left ventricular remodeling at 7 days after myocardial infarction, was prevented by endothelial nitric oxide synthase. Capillary density, as identified by alpha-smooth muscle actin immunostaining, was significantly increased in the infarcted myocardium after endothelial nitric oxide synthase transfer compared with myocardial infarction control. All cardioprotective effects of endothelial nitric oxide synthase were blocked by N(omega)-nitro-l-arginine methyl ester administration, indicating a nitric-oxide-mediated event.


CONCLUSIONS
These results demonstrate that the endothelial nitric oxide synthase/nitric oxide system provides cardiac protection after myocardial infarction injury through inhibition of cardiac apoptosis, stimulation of neovascularization, and suppression of tumor growth factor beta1/Smad-2 signaling.
Chen
Lei-Lei
LL
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China.
Yin
Hang
H
Huang
Jun
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology*
D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D052250:Nitric Oxide Synthase Type III; D053148:Caspase 3