Abstract-Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction. Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptors (TLRs) serve as pattern recognition receptors within the innate immune system. Activation of TLR4 results in an inflammatory response and is involved in extracellular matrix degradation, both key processes of LV remodeling following myocardial infarction. To establish the role of TLR4 in postinfarct LV remodeling, myocardial infarction was induced in wild-type BALB/c mice and TLR4-defective C3H-Tlr4 LPSϪd mice. Without affecting infarct size, TLR4 defectiveness reduced the extent of LV remodeling (end-diastolic volume: 103.7Ϯ6.8 L versus 128.5Ϯ5.7 L; PϽ0.01) and preserved systolic function (ejection fraction: 28.2Ϯ3.1% versus 16.6Ϯ1.3%; PϽ0.01), as assessed by MRI. In the noninfarcted area, interstitial fibrosis, and myocardial hypertrophy were reduced in C3H-Tlr4LPSϪd mice. In the infarcted area, however, collagen density was increased, which was accompanied by fewer macrophages, reduced inflammation regulating cytokine expression levels (interleukin [IL]-1␣, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor-␣, interferon-␥, granulocyte/macrophage colony-stimulating factor), and reduced matrix metalloproteinase-2 (4684Ϯ515 versus 7573Ϯ611; Pϭ0.002) and matrix metalloproteinase-9 activity (76.0Ϯ14.3 versus 168.0Ϯ36.2; Pϭ0.027). These data provide direct evidence for a causal role of TLR4 in postinfarct maladaptive LV remodeling, probably via inflammatory cytokine production and matrix degradation. TLR4 may therefore constitute a novel target in the treatment of ischemic heart failure.
Background-Toll-like receptor 4 (Tlr4) is the receptor for exogenous lipopolysaccharides (LPS). Expression of endogenous Tlr4 ligands, heat shock protein 60 (Hsp60) and extra domain A of fibronectin, has been observed in arthritic and oncological specimens in which matrix turnover is an important feature. In atherosclerosis, outward remodeling is characterized by matrix turnover and a structural change in arterial circumference and is associated with a vulnerable plaque phenotype. Since Tlr4 ligands are expressed during matrix turnover, we hypothesized that Tlr4 is involved in arterial remodeling. Methods and Results-In a femoral artery cuff model in the atherosclerotic ApoE3 (Leiden) transgenic mouse, Tlr4 activation by LPS stimulated plaque formation and subsequent outward arterial remodeling. With the use of the same model in wild-type mice, neointima formation and outward remodeling occurred. In Tlr4-deficient mice, however, no outward arterial remodeling was observed independent of neointima formation. Carotid artery ligation in wild-type mice resulted in outward remodeling without neointima formation in the contralateral artery. This was associated with an increase in Tlr4 expression and EDA and Hsp60 mRNA levels. In contrast, outward remodeling was not observed after carotid ligation in Tlr4-deficient mice. Conclusions-These findings provide genetic evidence that Tlr4 is involved in outward arterial remodeling, probably through upregulation of Tlr4 and Tlr4 ligands.
The family of Toll-like receptors ( TLRs) initiates an innate immune response after recognition of pathogen-associated molecular patterns (PAMPs). Evidence is accumulating that TLRs, and particularly TLR4, are important players in the initiation and progression of atherosclerotic disease. Not only exogenous ligands but also endogenous ligands that are expressed during arterial injury are recognized by TLR4. Mouse knockout studies and epidemiological studies of human TLR4 polymorphisms have demonstrated that the TLR4 might play a role in the initiation and progression of atherosclerosis. This review will summarize the latest progression in research on the role of TLR4 in arterial occlusive disease In addition, the potential of intervention in TLR4 signalling to influence progression of atherosclerotic disease is discussed.
Abstract-Myocardial infarction is commonly complicated by left ventricular remodeling, a process that leads to cardiac dilatation, congestive heart failure and death. The innate immune system plays a pivotal role in the remodeling process via nuclear factor (NF)-B activation. The NF-B transcription factor family includes several subunits (p50, p52, p65, c-Rel, and Rel B) that respond to myocardial ischemia. Key Words: myocardial infarction Ⅲ ischemic heart disease Ⅲ remodeling Ⅲ NF-B Ⅲ wound healing M yocardial infarction (MI) is commonly complicated by maladaptive left ventricular (LV) remodeling, which refers to alterations in LV chamber mass, geometry, and function. 1 Remodeling is a chronic process, mediated by progressive structural changes in cardiomyocytes and the extracellular matrix (ECM), leading to LV dilatation and impaired systolic function, and potentiates the development of ventricular arrhythmias, heart failure, and subsequent cardiovascular mortality. 2-4 Recently, we have shown that deletion of Toll-like receptor 4 limits ventricular remodeling and improves cardiac function after MI, identifying the innate immune system as a major player in the myocardial response to ischemic injury. 5 Toll-like receptors serve as pattern-recognition receptors within the innate immune system and elicit an inflammatory response via nuclear factor (NF)-B.The NF-B/Rel family regulates transcription via binding to a common decameric sequence motif known as the B site. Members of the NF-B family (p50, p52, p65, c-Rel, and Rel B) share a conserved Rel homology domain and form homoor heterodimers (most commonly p50/p65, p50/p50, or p65/ p65) that are located in the cytosol and are bound to inhibitory IB proteins. Activation of NF-B can be triggered by a variety of stimuli including proinflammatory cytokines, oxidative stress, bacterial and viral products, and also ischemia. 6 -9 Activation leads to rapid phosphorylation, ubiquitination, and subsequent degradation of IB-␣. This allows translocation of the dimer into the nucleus, where it can initiate NF-B-dependent transcription of a large and diverse array of target genes that modulate various physiological and pathological processes, including MI.Following MI, activation of NF-B mediates maladaptive LV remodeling and functional deterioration. 10 Blocking of NF-B activity was therefore suggested to be a promising novel approach to prevent adverse LV remodeling following MI. The role of the different NF-B subunits following MI, however, has not been completely clarified thus far. In this study, we investigate the role of the NF-B p50 subunit in LV Original
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.