Inflammation and postinfarct remodeling: Overexpression of IκB prevents ventricular dilation via increasing TIMP levels
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.
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.
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TL;DR: The complex network of cytokines and other biomolecules modulating inflammation in cardiovascular pathologies presents itself as promising target for the further improvement of existing and development of new therapeutic strategies.
Abstract: BACKGROUND: Inflammation of the cardiovascular system is an important pathogenic component of cardiac and/or vascular disease, which represents an enormous clinical burden in medicine. METHODS: Review. RESULTS: In this review, we will summarize basic science studies together with clinical studies, which have investigated the role of different cytokines, proteases, and growth factors in the inflammatory process in the cardiovascular system in the context of specific pathologies. Furthermore, therapeutic strategies to modulate inflammation in cardiovascular diseases will be discussed. CONCLUSIONS: The complex network of cytokines and other biomolecules modulating inflammation in cardiovascular pathologies presents itself as promising target for the further improvement of existing and development of new therapeutic strategies. Therefore further intensive research in this area seems highly warranted.
14 citations
Cites background from "Inflammation and postinfarct remode..."
...tively influences ECM remodelling in animal model [56]....
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TL;DR: Findings indicate that the repression of TNF-α associated with moderate hypothermia during cardiac surgery is associated with inhibition of the mitogen-activated protein kinase p38/activating protein-1 pathway and not with inhibited NF-κB.
Abstract: Introduction
The use of moderate hypothermia during experimental cardiac surgery is associated with decreased expression of tumour necrosis factor (TNF)-α in myocardium and with myocardial protection. In order to identify the cellular mechanisms that lead to that repression, we investigated the effect of hypothermia during cardiac surgery on both main signalling pathways involved in systemic inflammation, namely the nuclear factor-κB (NF-κB) and activating protein-1 pathways.
13 citations
Cites background from "Inflammation and postinfarct remode..."
...Indeed, there is a large body of evidence that, in experimental models, over-expression of TNF-α in the myocardium is related to adverse cardiac effects such as postinfarct remodelling and ventricular dilatation [4], transition from hypertrophic to dilated cardiomyopathy due to apoptosis [5] and impaired postischaemic functional recovery [6]....
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TL;DR: Acute endothelin-A receptor blockade is superior to chronic blockade in attenuating ischemia/reperfusion injury in failing hearts and might be an interesting option for patients with heart failure undergoing cardiac surgery.
12 citations
Cites methods from "Inflammation and postinfarct remode..."
...Therefore, at the end of the ex vivo experiment, 5 random hearts from each group underwent morphometric examination.(13) Infarct size was expressed as the ratio of the infarct region to total LV mass....
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TL;DR: The role of metoprolol in ameliorating sympathetic sprouting in rabbits after myocardial infarction is evaluated and is associated in part with inhibiting NF-κB activity.
Abstract: Objectives: Systemic or local inflammation causes cardiac nerve sprouting and consequent arrhythmia. Metoprolol can prevent sympathetic nerve remodeling after myo
11 citations
TL;DR: Imidapril had a superior effect for preventing ventricular remodeling characterized by fibrosis and collagen accumulation in left ventricle compared with ramipril in the moderate and large MI groups, even though the dosage used in this study was too small to reduce systemic blood pressure.
Abstract: Background:Angiotensin converting enzyme inhibitors have been used clinically to prevent myocardial infarction (MI). The angiotensin converting enzyme inhibitors attenuated ventricular remodeling and improved cardiac function by inhibition of matrix metalloproteinases after MI. Although the effect i
10 citations
Cites background from "Inflammation and postinfarct remode..."
...Inflammatory factors like TNF-a lead to the activation of MMPs and downregulated TIMP expression.(28) Overexpression of cytokines damages cardiac tissue and evokes excess deposition of fibrotic factors, even in the noninfarct area....
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References
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TL;DR: In this paper, a review of recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK is presented, focusing on recent progress and unanswered questions.
3,342 citations
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.
2,815 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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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.
1,966 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]....
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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.
988 citations
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.
935 citations