Macrophage Migration Inhibitory Factor Provides Cardioprotection During Ischemia/Reperfusion by Reducing Oxidative Stress

Koga, Kayoko; Kenessey, Ágnes; Powell, Saul R.; Sison, Cristina; Miller, Edmund J.; Ojamaa, Kaie

doi:10.1089/ars.2010.3163

Cited by 111 publications

(120 citation statements)

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“…Previous studies demonstrated that following MI, MIF is immediately released from injured cardiomyocytes, providing predominately protective properties through its receptor, CD74, and its antioxidant capacity 27, 59, 60. In contrast, a second delayed wave of MIF derived from infiltrating immune cells contributes to aggravation of cardiac function and adverse cardiac remodeling, presumably mainly through CXCR2 and CXCR4 59.…”

Section: Discussionmentioning

confidence: 99%

“…Cardioprotection by MIF is mediated through its intrinsic antioxidant capacity and by signaling through its cognate receptor CD74, a type II transmembrane glycoprotein and the surface form of class II invariant chain 25, 26, 27, 28, 29, 30, 31. In fact, The MIF/CD74/AMPK (adenosine monophosphate kinase) signaling pathway has repeatedly been demonstrated to play a pivotal protective role in acute myocardial ischemia/reperfusion injury 31, 32, 33.…”

Section: Introductionmentioning

confidence: 99%

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Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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BackgroundAlthough macrophage migration inhibitory factor (MIF) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD74, the function of the soluble CD74 receptor ectodomain (sCD74) and its interaction with circulating MIF have not been explored in cardiac disease.Methods and ResultsCardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD74 induced cell death (P<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (RIP)1/RIP3‐dependent necroptosis (P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT‐qPCR technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with sCD74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD74 as a modulator of MIF signaling by diminishing MIF‐mediated protein kinase B (AKT) activation (P=0.0197) and triggering p38 activation (P=0.0641). We obtained evidence that sCD74 inhibits MIF‐mediated survival pathway through the C‐X‐C chemokine receptor 4/AKT axis, enabling the induction of CD74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD74/MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).ConclusionsThese findings suggest that treatment of cardiac myofibroblasts with sCD74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD74/MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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“…After approximately 2 min of perfusion with dye, the heart was excised and sectioned along the short axis into five or six 2 mm slices that were incubated in 2,3,5-triphenyltetrazolium chloride solution (TTC, 1% in phosphate-buffered saline [PBS]; Sigma Aldrich) for 30 min at 37°C to define viable and nonviable tissue within the AAR. Infarct size and AAR were measured by one individual as previously described (23).…”

Section: Tissue Homogenization Fractionation and Immunoblot Analysismentioning

confidence: 99%

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

Mavropoulos

Khan

Levy

et al. 2017

Mol Med

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Reperfusion injury following acute myocardial infarction is associated with significant morbidity. Activation of neuronal or non-neuronal cholinergic pathways in the heart has been shown to reduce ischemic injury, and this effect has been attributed primarily to muscarinic acetylcholine receptors. In contrast, the role of nicotinic receptors, specifically α-7 subtype (α7nAChR), in the myocardium remains unknown, which offers an opportunity to potentially repurpose several agonists/modulators that are currently under development for neurologic indications. Treatment of ex vivo and in vivo rat models of cardiac ischemia/reperfusion (I/R) with a selective α7nAChR agonist (GTS21) showed significant increases in left ventricular developing pressure and rates of pressure development, without effects on heart rate. These positive functional effects were blocked by co-administration with methyllycaconitine (MLA), a selective antagonist of α7nAChRs. In vivo, delivery of GTS21 at the initiation of reperfusion reduced infarct size by 42% (p < 0.01) and decreased tissue reactive oxygen species (ROS) by 62% (p < 0.01). Flow cytometry of MitoTracker Red-stained mitochondria showed that mitochondrial membrane potential was normalized in mitochondria isolated from GTS21-treated compared with untreated I/R hearts. Intracellular adenosine triphosphate (ATP) concentration in cultured cardiomyocytes exposed to hypoxia/reoxygenation was reduced (p < 0.001), but significantly increased to normoxic levels with GTS21 treatment, which was abrogated by MLA pretreatment. Activation of stress-activated kinases JNK and p38MAPK was significantly reduced by GTS21 in I/R. We conclude that targeting myocardial α7nAChRs in I/R may provide therapeutic benefit by improving cardiac contractile function through a mechanism that preserves mitochondrial membrane potential, maintains intracellular ATP and reduces ROS generation, thus limiting infarct size. online address: http://www.molmed.org

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“…Mif regulates the release of proinflammatory mediators (9). In the heart, Mif is rapidly released in response to a cellular stressor, such as a brief hypoxia (25,42). Plasma Mif levels are increased in old healthy volunteers compared with young controls, and dietary nitrate supplementation caused a reduction of plasma Mif levels and improvement in vascular function (43).…”

Section: Ccl5 (M1)mentioning

confidence: 99%

Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization

Toba

Brás

Baicu

et al. 2015

American Journal of Physiology-Cell Physiology

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Toba H, de Castro Brás LE, Baicu CF, Zile MR, Lindsey ML, Bradshaw AD. Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization. Am J Physiol Cell Physiol 308: C972-C982, 2015. First published April 15, 2015; doi:10.1152/ajpcell.00402.2014.-To investigate the role of secreted protein acidic and rich in cysteine (SPARC) in age-related cardiac inflammation, we studied six groups of mice: young (3-5 mo old), middle-aged (10 -12 mo old), and old (18 -29 mo old) C57BL/6 wild-type (WT) and SPARC-null (Null) mice (n ϭ 7-10/group). Cardiac function and structure were determined by echocardiography. The left ventricle was used for cytokine gene array and macrophage quantification by immunohistochemistry. Macrophage infiltration increased with age in WT (n ϭ 5-6/group, P Ͻ 0.05 for young vs. old), but not in Null. Proinflammatory markers (Ccl5, Cx3cl1, Ccr2, and Cxcr3) increased in middle-aged and old WT, whereas they were increased only in old Null compared with respective young (n ϭ 5-6/group, P Ͻ 0.05 for all). These results suggest that SPARC deletion delayed age-related cardiac inflammation. To further assess how SPARC affects inflammation, we stimulated peritoneal macrophages with SPARC (n ϭ 4). SPARC treatment increased expression of proinflammatory macrophage M1 markers and decreased anti-inflammatory M2 markers. Echocardiography (n ϭ 7-10/group) revealed an age-related increase in wall thickness of the left ventricle in WT (0.76 Ϯ 0.02 mm in young vs. 0.91 Ϯ 0.03 mm in old; P Ͻ 0.05) but not in Null (0.78 Ϯ 0.01 mm in young vs. 0.84 Ϯ 0.02 mm in old). In conclusion, SPARC deletion delayed age-related increases in macrophage infiltration and proinflammatory cytokine expression in vivo and in vitro. SPARC acts as an important mediator of age-related cardiac inflammation by increasing the expression of macrophage M1 markers and decreasing M2 markers.

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Macrophage Migration Inhibitory Factor Provides Cardioprotection During Ischemia/Reperfusion by Reducing Oxidative Stress

Cited by 111 publications

References 50 publications

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization

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