Neutralization of interleukin-1β in the acute phase of myocardial infarction promotes the progression of left ventricular remodeling

Hwang, Myung-Woo; Matsumori, Akira; Furukawa, Yutaka; Ono, Koh; Okada, Masaharu; Iwasaki, Atsushi; Hara, Masatake; Miyamoto, Tadashi; Touma, Masanao; Sasayama, Shígetake

doi:10.1016/s0735-1097(01)01591-1

Cited by 137 publications

(104 citation statements)

References 27 publications

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“…Earlier studies showed deleterious consequences (including a worsening of ventricular remodeling) following inhibition of fibrotic healing or the inflammatory response after infarction by means of corticosteroids. 29,30 Recent research on genetically modified mice has also demonstrated the adverse consequences of impaired fibrotic healing after MI leading to aggravated ventricular rupture and remodeling, 31,32 although the suppression of excessive matrix deposition is believed to be beneficial in the context of stem cell based therapies. Our findings showed that fibrotic healing post-infarction can be therapeutically remodeled by relaxin leading to a reduced density of fibrotic tissue across infarcted, non-infarcted, and border zones.…”

Section: Discussionmentioning

confidence: 99%

Relaxin remodels fibrotic healing following myocardial infarction

Samuel

Cendrawan

Gao

et al. 2011

Laboratory Investigation

101

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In the setting of myocardial infarction (MI), implanted stem cell viability is low and scar formation limits stem cell homing, viability, and integration. Thus, interventions that favorably remodel fibrotic healing may benefit stem cell therapies. However, it remains unclear whether it is feasible and safe to remodel fibrotic healing post-MI without compromising ventricular remodeling and dysfunction. This study, therefore, determined the anti-fibrotic and other effects of the hormone, relaxin in a mouse model of MI. Adult male mice underwent left coronary artery ligation-induced MI and were immediately treated with recombinant human relaxin (MI þ RLX) or vehicle (MI þ VEH) over 7 or 30 days, representing time points of early and mature fibrotic healing. Cardiac function was assessed by echocardiography and catheterization, while comprehensive immunohistochemistry, morphometry, and western blotting were performed to explore the relaxin-induced mechanisms of action post-MI. RLX significantly inhibited the MI-induced progression of cardiac fibrosis over 7 and 30 days, which was associated with a reduction in TGF-b1 expression, myofibroblast differentiation, and cardiomyocyte apoptosis in addition to a promotion of matrix metalloproteinase-13 levels and de novo blood vessel growth (all Po0.05 vs respective measurements from MI þ VEH mice). Despite the evident fibrotic healing post-MI, relaxin did not adversely affect the incidence of ventricular free-wall rupture or the extent of LV remodeling and dysfunction. These combined findings demonstrate that RLX favorably remodels the process of fibrotic healing post-infarction by lowering the density of mature scar tissue in the infarcted myocardium, border zone, and non-infarcted myocardium, and may, therefore, facilitate cell-based therapies in the setting of ischemic heart disease.

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Section: Discussionmentioning

confidence: 99%

Relaxin remodels fibrotic healing following myocardial infarction

Samuel

Cendrawan

Gao

et al. 2011

Laboratory Investigation

101

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“…Cardiac transfection with human IL-1Ra significantly decreased infarct size, reduced apoptosis, and attenuated the inflammatory response in rat hearts undergoing ischemia/ reperfusion protocols [160], suggesting an injurious role for IL-1 in the ischemic myocardium. In contrast, another investigation suggested a protective role for IL-1 demonstrating that IL-1β neutralization in the acute phase of myocardial infarction resulted in increased occurrence of cardiac rupture and enhanced adverse remodeling [161]. Because IL-1 signals exclusively through the IL-1 receptor type I (IL-1RI) we have recently examined the effects of disrupted IL-1 signaling on infarct healing and cardiac remodeling using IL-1RI −/− mice [162].…”

Section: The Il-1 Familymentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

567

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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“…Animal experiments showed that a neutralizing antibody against IL-1β and Anakinra, a recombinant IL-1 receptor antagonist (IL-1RA), exerted beneficial effects on acute MI. 28,29) Furthermore, inflammatory responses can occur more aggressively in myocardial I/R compared with permanent MI. 1) These fi ndings allow us to assume that inflammasomes may play a substantial role in the pathophysiology of myocardial I/R injury.…”

Section: Nlrp3 Inflammasome and Myocardial Infarction (Mi)mentioning

confidence: 99%

“…Second, because inflammation also plays a critical role in the process of cardiac healing after MI, inhibition of infl ammation may infl uence cardiac rupture and aneurysm formation. An initial study by Hwang, et al 28) suggested that neutralization of IL-1β reduced collagen accumulation in the heart after experimental MI and increased the occurrence of cardiac rupture. However, impaired cardiac healing and increased rupture after MI were not observed in the studies using genetic deletion of IL-1 receptor or pharmacological blockades (Anakinra or IL-1 trap [rilonacept]).…”

Section: Nlrp3 Inflammasome and Myocardial Infarction (Mi)mentioning

confidence: 99%

NLRP3 Inflammasome as a Novel Player in Myocardial Infarction

2014

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SummaryInfl ammasomes are multiple protein complexes that serve as molecular platforms to activate caspase-1 and regulate maturation of a potent proinfl ammatory cytokine, interleukin (IL)-1β, as well as proinfl ammatory cell death, pyroptosis. Although several types of infl ammasomes have been reported so far, recent investigations indicate that the NLRP3 infl ammasome recognizes non-microbial danger signals and leads to sterile infl ammatory responses in various disease conditions. Sterile infl ammatory responses are also implicated in the development of myocardial infarction (MI). In particular, IL-1β is an early and prominent mediator of infl ammatory responses in MI, suggesting the pathophysiologic role of NLRP3 infl ammasomes in MI. This review highlights the current state of knowledge regarding the role of NLRP3 infl ammasomes in MI. (Int Heart J 2014; 55: 101-105)

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Neutralization of interleukin-1β in the acute phase of myocardial infarction promotes the progression of left ventricular remodeling

Abstract: Anti-IL-1beta treatment suppressed pro-collagen gene expression and delayed wound healing mechanisms-properties that are likely to lead to progression of LV remodeling. In the acute phase of MI, IL-1beta appears to play a protective role.

Cited by 137 publications

References 27 publications

Relaxin remodels fibrotic healing following myocardial infarction

Relaxin remodels fibrotic healing following myocardial infarction

The immune system and cardiac repair

NLRP3 Inflammasome as a Novel Player in Myocardial Infarction

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