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Journal ArticleDOI

Inflammation and postinfarct remodeling: Overexpression of IκB prevents ventricular dilation via increasing TIMP levels

15 Feb 2006-Cardiovascular Research (Cardiovasc Res)-Vol. 69, Iss: 3, pp 746-754

TL;DR: 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.

AbstractObjective: 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.

Topics: Ventricular remodeling (57%)

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Citations
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Journal ArticleDOI
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.
Abstract: In adult mammals, massive sudden loss of cardiomyocytes after infarction overwhelms the limited regenerative capacity of the myocardium, resulting in the formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of proinflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand 2 [CCL2]). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin–angiotensin–aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response after myocardial infarction. Dysregulation of immune pathways, impaired suppression of postinfarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.

783 citations


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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.
Abstract: Peroxynitrite is a potent oxidant and nitrating species formed from the reaction between the free radicals nitric oxide and superoxide. An excessive formation of peroxynitrite represents an important mechanism contributing to cell death and dysfunction in multiple cardiovascular pathologies, such as myocardial infarction, heart failure and atherosclerosis. Whereas initial works focused on direct oxidative biomolecular damage as the main route of peroxynitrite toxicity, more recent evidence, mainly obtained in vitro, indicates that peroxynitrite also behaves as a potent modulator of various cell signal transduction pathways. Due to its ability to nitrate tyrosine residues, peroxynitrite affects cellular processes dependent on tyrosine phosphorylation. Peroxynitrite also exerts complex effects on the activity of various kinases and phosphatases, resulting in the up- or downregulation of signalling cascades, in a concentration- and cell-dependent manner. Such 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.

177 citations


Cites result from "Inflammation and postinfarct remode..."

  • ...Comparable results have been obtained using a strategy of myocardial overexpression of IkappaBalpha by adenovirusmediated transfection in rats (107)....

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Journal ArticleDOI
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.
Abstract: Mitochondria are indispensable for bioenergetics and for the regulation of physiological/signaling events in cellular life. Although TNF-α-induced oxidative stress and mitochondrial dysfunction are...

151 citations


Journal ArticleDOI
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.
Abstract: The myocardial extracellular matrix (ECM), which preserves the geometry and integrity of the myocardium, is a dynamic structure whose component proteins are maintained by a finely controlled homeostatic balance between deposition and degradation. One of the key targets in cardiology is the elucidation of the molecular mechanisms which mediate pathological remodelling of this matrix causing the transition from compensatory hypertrophy to congestive decompensated heart failure. In response to injury or increased workload, cardiac remodelling including myocyte hypertrophy, develops as the heart attempts to compensate for increased wall stresses. Persistence of these stresses over extended time periods leads to disruption of ECM homeostasis resulting in irreversible maladaptive cardiac remodelling, ventricular dilatation and finally heart failure. ECM remodelling is regulated by the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs). Clinical studies and experimental models of cardiac disease states have reported alterations in the balance between the MMPs and TIMPs in the failing heart and crucially at intermediate time points in the progression to failure. This article reviews the recent clinical, genetic and experimental approaches employed to compare ECM, MMP and TIMP profiles in healthy, compensated and failing hearts and identifies common themes in the perturbation of ECM homeostasis in the transition to heart failure.

100 citations


Cites background from "Inflammation and postinfarct remode..."

  • ...…of this, limited left ventricular dilation and reduced expression of MMP-2 and MMP-9 was observed in rats overexpressing the endogenous inhibitor (IjB) of the NF-jB transcription factor (which regulates MMP-2 and 9 gene transcription) following coronary artery ligation (Trescher et al. 2006)....

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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.
Abstract: Objective Accumulated evidence suggests that the primary cause of poor outcome after subarachnoid hemorrhage (SAH) is not only cerebral arterial narrowing, but also early brain injury (EBI). Our objective was to determine the effect of recombinant osteopontin (r-OPN), a pleiotropic extracellular matrix glycoprotein, on post-SAH EBI in rats.

96 citations


References
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Journal ArticleDOI
19 Apr 2002-Cell
Abstract: The regulation of the transcription factor NF-kappaB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-kappaB regulation is the IkappaB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK.

3,237 citations


Journal ArticleDOI
TL;DR: The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival.
Abstract: An acute myocardial infarction, particularly one that is large and transmural, can produce alterations in the topography of both the infarcted and noninfarcted regions of the ventricle. This remodeling can importantly affect the function of the ventricle and the prognosis for survival. In the early period, infarct expansion has been recognized by echocardiography as a lengthening of the noncontractile region. The noninfarcted region also undergoes an important lengthening that is consistent with a secondary volume-overload hypertrophy and that can be progressive. The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival. The process of ventricular enlargement can be influenced by three interdependent factors, that is, infarct size, infarct healing, and ventricular wall stresses. A most effective way to prevent or minimize the increase in ventricular size after infarction and the consequent adverse effect on prognosis is to limit the initial insult. Acute reperfusion therapy has been consistently shown to result in a reduction in ventricular volume. The reestablishment of blood flow to the infarcted region, even beyond the time frame for myocyte salvage, has beneficial effects in attenuating ventricular enlargement. The process of scarification can be interfered with during the acute infarct period by the administration of glucocorticosteroids and nonsteroidal antiinflammatory agents, which result in thinner infarcts and greater degrees of infarct expansion. Modification of distending or deforming forces can importantly influence ventricular enlargement. Even short-term augmentations in afterload have deleterious long-term effects on ventricular topography. Conversely, judicious use of nitroglycerin seems to be associated with an attenuation of infarct expansion and long-term improvement in clinical outcome. Long-term therapy with an angiotensin converting enzyme inhibitor can favorably alter the loading conditions on the left ventricle and reduce progressive ventricular enlargement as demonstrated in both experimental and clinical studies. With the former therapy, this attenuation of ventricular enlargement was associated with a prolongation in survival. The long-term clinical consequences of long-term angiotensin converting enzyme inhibitor therapy after myocardial infarction is currently being evaluated. Although studies directed at attenuating left ventricular remodeling after infarction are in the early stages, it does seem that this will be an important area in which future research might improve long-term outcome after infarction.

2,730 citations


"Inflammation and postinfarct remode..." refers background in this paper

  • ...Experimental and clinical failure of different approaches blocking the inflammatory cascade in the first hours after the ischemic injury demonstrated the importance of inflammation for infarct stabilization and wound healing [25]....

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Journal ArticleDOI
TL;DR: This review summarizes the current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion and concludes that by promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling.
Abstract: One of the major therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial necrosis and optimizing cardiac repair following myocardial infarction. However, a sound understanding of the biology is necessary before a specific intervention is pursued on a therapeutic basis. This review summarizes our current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion. Myocardial necrosis induces complement activation and free radical generation, triggering a cytokine cascade initiated by Tumor Necrosis Factor (TNF)-α release. If reperfusion of the infarcted area is initiated, it is attended by an intense inflammatory reaction. Interleukin (IL)-8 synthesis and C5a activation have a crucial role in recruiting neutrophils in the ischemic and reperfused myocardium. Neutrophil infiltration is regulated through a complex sequence of molecular steps involving the selectins and the integrins, which mediate leukocyte rolling and adhesion to the endothelium. Marginated neutrophils exert potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. Despite this potential injury, substantial evidence suggests that reperfusion enhances cardiac repair improving patient survival; this effect may be in part related to the inflammatory response. Monocyte Chemoattractant Protein (MCP)-1 is also markedly upregulated in the infarcted myocardium inducing recruitment of mononuclear cells in the injured areas. Monocyte-derived macrophages and mast cells may produce cytokines and growth factors necessary for fibroblast proliferation and neovascularization, leading to effective repair and scar formation. At this stage expression of inhibitory cytokines such as IL-10 may have a role in suppressing the acute inflammatory response and in regulating extracellular matrix metabolism. Fibroblasts in the healing scar undergo phenotypic changes expressing smooth muscle cell markers. Our previous review in this journal focused almost exclusively on reduction of the inflammatory injury. The current update is prompted by the potential therapeutic opportunity that the open vessel offers. By promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling, that is the leading cause of heart failure and death. Elucidating the complex interactions and regulatory mechanisms responsible for cardiac repair may allow us to design effective inflammation-related interventions for the treatment of myocardial infarction.

1,886 citations


"Inflammation and postinfarct remode..." refers background in this paper

  • ...Acute MI starts a cytokine cascade in both the infarcted and non-infarcted myocardium via complement activation and reactive oxygen species [1–3]....

    [...]


Journal ArticleDOI
TL;DR: It is shown that the transcription factor NF-κB has been shown to be the target of several anti-inflammatory and anticancer drugs.
Abstract: Beginning with its discovery in 1986 and continuing through the present, the transcription factor NF-κB has attracted widespread interest based on its unusual regulation, the variety of stimuli that activate it, the diverse genes and biological responses that it controls, the striking evolutionary conservation of structure and function among family members, and its apparent involvement in a variety of human diseases (Table ​(Table1).1). Importantly, and consistent with the last point, NF-κB has been shown to be the target of several anti-inflammatory and anticancer drugs.

951 citations


Book ChapterDOI
TL;DR: The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival.
Abstract: Acute transmural myocardial infarction initiates a series of changes in left ventricular (LV) volume, regional function and geometry. This process, known as postinfarction LV remodeling, may continue for months or years following the initial ischemic event. To characterize the components of late ventricular remodeling, biplane left ventriculography was performed in 52 patients at 3 weeks and repeated at 1 year after first anterior myocardial infarction. Biplane circumference and contractile and noncontractile segment lengths were measured. Global geometry was evaluated by calculating a sphericity index and regional geometry was assessed by measurement of endocardial curvature. End-diastolic (ED) volume was increased at 3 weeks and enlarged further at one year. This late enlargement was accompanied by an increase in the length of the contractile segment and an increase in sphericity, whereas the length of the noncontractile segment decreased. Curvature analysis revealed that this late increase in sphericity resulted from flattening of regions of presumably high tension negative curvature at the infarct border zone and from less bulging of the infarcted anterior wall. Even in patients selected for late ventricular enlargement (change in ED volume > 20 ml, n = 19), this increase in volume resulted from both lengthening of the contractile segment and an increase in sphericity without a change in the noncontractile segment length. Thus, late ventricular enlargement after anterior myocardial infarction results from an increase in contractile segment length and a change in ventricular geometry and is not a result of progressive infarct expansion.

930 citations