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  • Title: Inflammation and postinfarct remodeling: overexpression of IkappaB prevents ventricular dilation via increasing TIMP levels.
    Author: Trescher K, Bernecker O, Fellner B, Gyöngyösi M, Schäfer R, Aharinejad S, DeMartin R, Wolner E, Podesser BK.
    Journal: Cardiovasc Res; 2006 Feb 15; 69(3):746-54. PubMed ID: 16388787.
    Abstract:
    OBJECTIVE: Nuclear factor-kappa B (NF-kappaB) 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 IkappaB, the natural inhibitor of NF-kappaB, 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 IkappaB (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 IkappaB group compared to LacZ. NF-kappaB 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)-alpha and interleukin (IL)-1beta 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-kappaB activity via IkappaB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and -9 levels while increasing TIMP-1, -2, -3, and -4 levels. Therefore, IkappaB overexpression prevents ventricular dilation and consequently preserves cardiac function.
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