Adenovirus-mediated overexpression of inhibitor kappa B-alpha attenuates postinfarct remodeling in the rat heart.
OBJECTIVE
The transcription factor nuclear factor kappa B (NF-kB) plays an important role in the inflammatory response following myocardial infarction. We hypothesized that NF-kB-blockade in an animal model of acute ischemia reduces the inflammatory response and therefore attenuates ventricular remodeling.


METHODS
Myocardial infarcts (MI) were produced in male Sprague-Dawley rats by ligation of the LAD and followed by adenovirus-mediated intramyocardial delivery of inhibitor kappa Balpha-gene (n=10), the physiological inhibitor of the transcription factor nuclear factor kappa B, respectively, of a beta-gal reporter-gene (n=11). Sham-operated animals (n=10) received neither ligation nor gene transfer. Five days after MI IkB-expression levels were determined by western blotting. Seven weeks after MI in vivo cardiac function was evaluated by transthoracic echocardiography. Based on left ventricular endsystolic and enddiastolic diameters ejection fraction and fractional shortening were calculated. Only animals with MI involving more than 30% of the left ventricle were included. Data are given as mean+/-SD.


RESULTS
In IkBalpha-transfected hearts IkBalpha-levels were six-fold higher (P<0.05) than in beta-gal transfected hearts. Concerning in vivo hemodynamics IkBalpha-treated hearts showed reduced systolic and diastolic left ventricular dimensions compared to the beta-gal MI-group (systolic 48+/-4 vs. 66+/-3 mm; diastolic 67+/-5 vs. 84+/-6 mm; P<0.01). Consequently fractional shortening (27.8+/-1.5 vs. 20.4+/-4.0%; P<0.01) and ejection fraction (63.4+/-3.6 vs. 49.1+/-8.3%; P<0.05) were preserved in IkBalpha hearts compared to beta-gal MI-hearts.


CONCLUSIONS
It can be concluded that overexpression of IkBalpha leads to an improved cardiac function thereby attenuating postinfarct remodeling.
Trescher
Karola
K
Ludwig Boltzmann Institute for Cardiosurgical Research, Medical University of Vienna, Vienna, Austria.
Bernecker
Oliver
O
Fellner
Barbara
B
Gyöngyösi
Marian
M
Krieger
Sigurd
S
Demartin
Rainer
R
Wolner
Ernst
E
Podesser
Bruno K
BK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006439:Hemodynamics; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha