Macrophage migration inhibitory factor induces cardiomyocyte apoptosis

Dhanantwari, Preeta; Nadaraj, Sumekala; Kenessey, Ágnes; Chowdhury, Devyani; Al‐Abed, Yousef; Miller, Edmund J.; Ojamaa, Kaie

doi:10.1016/j.bbrc.2008.04.070

Cited by 25 publications

(24 citation statements)

References 37 publications

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“…[31][32][33] However, MIF acts as a pro-apoptotic molecule as well through engaging mitochondriarelated apoptotic pathway. [25][26][27][28] The initial step in the apoptosis induction is assembling of BAX molecules into large homo-oligomers that damage the outer mitochondrial membrane, consequently becoming permeable to proteins normally constrained within the intermembrane space of the mitochondria. On the other hand, presence of Bcl-2 proteins confronts membrane pore formation.…”

Section: Discussionmentioning

confidence: 99%

“…26 Additionally, MIF activates caspase 3, BAX and MAPK, all of which may be involved in apoptosis induction in different cell types and different settings. 28,29 As MIF is implicated in diabetes pathogenesis, this study explored its local and systemic production and expression during high-fat diet (HFD)-induced T2D in C57BL/6 mice. Further, we investigated whether inhibition of this pro-inflammatory mediator could affect lipid-induced pancreatic islet or b cell apoptosis in vitro.…”

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confidence: 99%

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Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

et al. 2011

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As a result of chronic exposure to high levels of free fatty acids, glucose and inflammatory mediators b-cell apoptosis occurs at the end stage of obesity-associated type 2 diabetes (T2D). One potentially deleterious molecule for b-cell function associated with T2D and obesity in humans is macrophage migration inhibitory factor (MIF). Therefore, the aim of this study was to explore MIF expression in vivo during development of obesity and insulin resistance in high-fat diet (HFD)-fed C57BL/6 mice and whether MIF inhibition could affect b-cell apoptosis and dysfunction induced by palmitic acid (PA) in vitro. Indeed, increase in systemic and locally produced MIF correlated well with the weight gain, triglyceride upregulation, glucose intolerance and insulin resistance, which developed in HFD-fed mice. In in vitro settings PA dose-dependently induced MIF secretion before apoptosis development in islets. Further, mif gene deletion, mRNA silencing or protein inhibition rescued b-cells from PA-induced apoptosis as measured by MTT assay and histone-DNA enzyme linked immuno sorbent assay. Protection from induced apoptosis was mediated by altered activation of caspase pathway and correlated with changes in the level of Bcl-2 family members. Further, MIF inhibition conveyed a significant resistance to PA-induced downregulation of insulin and PDX-1 expression and ATP content. However, b-cell function was not entirely preserved in the absence of MIF judging by low glucose oxidation and depolarized mitochondrial membrane. In conclusion, the observed considerable preservation of b-cells from nutrient-induced apoptosis might implicate MIF as a potential therapeutic target in the later stage of obesity-associated T2D.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

et al. 2011

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“…These effects of MIF on JNK activation were paralleled by suppression (16,17) or stimulation (18,19) of apoptosis. How these cellular effects of MIF relate to its action in intact organs remains uncertain but has relevance to understanding injury during ischemia/reperfusion.…”

Section: Introductionmentioning

confidence: 87%

“…The duration of MIF exposure might be important in determining its effect. Prolonged incubation with MIF appears to increase JNK phosphorylation and cell apoptosis in neonatal cardiomyocytes (19). LDL cholesterol increases MIF expression and JNK activation in human mesangial cells (31).…”

Section: Figurementioning

confidence: 98%

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Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion

Qi¹,

Hu²,

Wu³

et al. 2009

J. Clin. Invest.

163

172

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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that also modulates physiologic cell signaling pathways. MIF is expressed in cardiomyocytes and limits cardiac injury by enhancing AMPK activity during ischemia. Reperfusion injury is mediated in part by activation of the stress kinase JNK, but whether MIF modulates JNK in this setting is unknown. We examined the role of MIF in regulating JNK activation and cardiac injury during experimental ischemia/reperfusion in mouse hearts. Isolated perfused Mif -/-hearts had greater contractile dysfunction, necrosis, and JNK activation than WT hearts, with increased upstream MAPK kinase 4 phosphorylation, following ischemia/reperfusion. These effects were reversed if recombinant MIF was present during reperfusion, indicating that MIF deficiency during reperfusion exacerbated injury. Activated JNK acts in a proapoptotic manner by regulating BCL2-associated agonist of cell death (BAD) phosphorylation, and this effect was accentuated in Mif -/-hearts after ischemia/reperfusion. Similar detrimental effects of MIF deficiency were observed in vivo following coronary occlusion and reperfusion in Mif -/-mice. Importantly, excess JNK activation also was observed after hypoxia-reoxygenation in human fibroblasts homozygous for the MIF allele with the lowest level of promoter activity. These data indicate that endogenous MIF inhibits JNK pathway activation during reperfusion and protects the heart from injury. These findings have clinical implications for patients with the low-expression MIF allele.

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Inflammatory mechanisms and intervention strategies for sepsis‐induced myocardial dysfunction

Nong

Wei

2023

Immunity Inflam & Disease

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Sepsis‐induced myocardial dysfunction (SIMD) is the leading cause of death in patients with sepsis in the intensive care units. The main manifestations of SIMD are systolic and diastolic dysfunctions of the myocardium. Despite our initial understanding of the SIMD over the past three decades, the incidence and mortality of SIMD remain high. This may be attributed to the large degree of heterogeneity among the initiating factors, disease processes, and host states involved in SIMD. Previously, organ dysfunction caused by sepsis was thought to be an impairment brought about by an excessive inflammatory response. However, many recent studies have shown that SIMD is a consequence of a combination of factors shaped by the inflammatory responses between the pathogen and the host. In this article, we review the mechanisms of the inflammatory responses and potential novel therapeutic strategies in SIMD.

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Macrophage migration inhibitory factor induces cardiomyocyte apoptosis

Cited by 25 publications

References 37 publications

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion

Inflammatory mechanisms and intervention strategies for sepsis‐induced myocardial dysfunction

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