Copyright © 2005, European Society of Cardiology
Inflammation and postinfarct remodeling: Overexpression of I
B prevents ventricular dilation via increasing TIMP levels
aLudwig Boltzmann Institute for Cardiosurgical Research, Medical University of Vienna, c/o Institute of Biomedical Research, AKH-Wien, Währinger Gürtel 18-20, 1090 Vienna, Austria
bDepartment of Cardiology, Medical University of Vienna, Austria
cDepartment of Anatomy and Cell Biology, Medical University of Vienna, Austria
dDepartment of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria
eDepartment of Cardiothoracic Surgery, Medical University of Vienna, Austria
* Corresponding author. Tel.: +43 1 40400 5221; fax: +43 1 40400 5229. Email address: b.k.podesser{at}cardiovascular-research.at
Objective: Nuclear factor-kappa B (NF-
B) orchestrates genes involved in inflammation and extracellular matrix (ECM) remodeling following myocardial infarction (MI). The objective of the present study was to investigate the effect of overexpression and mode of function of IB, the natural inhibitor of NF-B, on ECM remodeling in a rat model of MI.
Methods: MI was induced in male Sprague-Dawley rats by ligation of the left anterior descending coronary artery (LAD) and was followed by adenovirus-mediated intramyocardial transfection of IB (n=26) or LacZ reporter genes (n=26). Sham-operated animals (n=14) served as controls.
Results: In transthoracic echocardiography 49 days after MI, systolic and diastolic left ventricular dimensions were reduced while fractional shortening was preserved in the treatment group. Additionally, evaluation on the isolated heart showed an attenuated downward shift of pressure–volume relationships in the IB group compared to LacZ. NF-B p65 DNA binding activity was diminished both at 5 and 49 days post-MI in the treatment group. Five days post-MI in the treatment group, protein levels of tumor necrosis factor (TNF)-
and interleukin (IL)-1β were significantly reduced by 72.6% and 73.2%, respectively, compared to LacZ (p<0.05). In parallel, matrix metalloproteinase (MMP)-2 and MMP-9 levels were reduced 5 days post-MI, with MMP-9 still being decreased 49 days post-MI (p<0.01). In contrast, tissue inhibitors of metalloproteinases (TIMP)-1, -2, and -3 were increased compared to LacZ (p<0.01 and p<0.05, respectively) 5 days post-MI. After 49 days, TIMP-2, -3, and -4 expressions were significantly elevated (p<0.05).
Conclusion: Reducing NF-B activity via IB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and -9 levels while increasing TIMP-1, -2, -3, and -4 levels. Therefore, IB overexpression prevents ventricular dilation and consequently preserves cardiac function.
KEYWORDS Myocardial infarction; Gene therapy; Nuclear factor-kappa B; Extracellular matrix remodelling
Time for primary review 21 days
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