Inflammation and postinfarct remodeling: Overexpression of IκB prevents ventricular dilation via increasing TIMP levels
Karola Trescher,Oliver Y. Bernecker,Barbara Fellner,M Gyongyosi,Romana Schäfer,Seyedhossein Aharinejad,Rainer DeMartin,Ernst Wolner,Bruno K. Podesser +8 more
TLDR
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.Abstract:
Objective: Nuclear factor-kappa B (NF-κB) 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 IκB, the natural inhibitor of NF-κB, 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 IκB ( 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 IκB group compared to LacZ. NF-κB 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)-α 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-κB activity via IκB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and -9 levels while increasing TIMP-1, -2, -3, and -4 levels. Therefore, IκB overexpression prevents ventricular dilation and consequently preserves cardiac function.read more
Citations
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The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis
TL;DR: The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts, and therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.
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Role of peroxynitrite in the redox regulation of cell signal transduction pathways.
TL;DR: Roles of peroxynitrite in the redox regulation of key signalling pathways for cardiovascular homeostasis, including protein kinase B and C, the MAP kinases, Nuclear Factor Kappa B, as well as signalling dependent on insulin and the sympatho-adrenergic system are presented in detail in this review.
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TNF-α-induced mitochondrial oxidative stress and cardiac dysfunction : restoration by superoxide dismutase mimetic Tempol
Nithya Mariappan,Rajasekaran Namakkal Soorappan,Masudul Haque,Srinivas Sriramula,Joseph Francis +4 more
TL;DR: The studies demonstrate that TNF-alpha-induced oxidative stress alters redox homeostasis by impairing the MPTP proteins adenine nucleotide translocator and voltage-dependent anion channel, thereby resulting in the pore opening, causing uncontrolled transport of substances to alter mitochondrial pH, and subsequently leading to dysfunction of mitochondria and attenuated cardiac function.
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Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats
Hidenori Suzuki,Robert Ayer,Takashi Sugawara,Wanqiu Chen,Takumi Sozen,Yu Hasegawa,Kenji Kanamaru,John H. Zhang +7 more
TL;DR: Treatment with recombinant osteopontin prevented a significant loss in body weight, neurologic impairment, brain edema, and blood–brain barrier disruption after subarachnoid hemorrhage.
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Extracellular matrix profiles in the progression to heart failure. European Young Physiologists Symposium Keynote Lecture-Bratislava 2007.
TL;DR: Clinical, genetic and experimental approaches employed to compare ECM, MMP and TIMP profiles in healthy, compensated and failing hearts are reviewed and common themes in the perturbation of ECM homeostasis in the transition to heart failure are identified.
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