Syndecan-4 Prevents Cardiac Rupture and Dysfunction After Myocardial Infarction

Matsui, Yutaka; Ikesue, Masahiro; Danzaki, Keiko; Morimoto, Junko; Sato, Mami; Tanaka, Shinya; Kojima, Tetsuhito; Tsutsui, Hiroyuki; Uede, Toshimitsu

doi:10.1161/circresaha.110.235689

Cited by 96 publications

(104 citation statements)

References 52 publications

(62 reference statements)

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“…This conclusion is supported by a recent clinical study demonstrating that low levels of the circulating receptor for advanced glycation end products ectodomain were associated with increased risk of HF 72. In contrast, overexpression of a syndecan‐4 ectodomain preceding MI induction augmented the incidence of cardiac rupture and impaired heart function, apparently attributed to impaired granulation tissue formation and reduced myofibroblast numbers 73. However, a synergistic effect of a soluble receptor ectodomain moiety and its ligand triggering cell death has not been described yet.…”

Section: Discussionmentioning

confidence: 68%

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: 68%

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

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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“…Findings by Matsui et al also support a role for syndecan-4 in this process, since they found impaired myofibroblast differentiation in the infarcted region after coronary ligation in syndecan-4 -/-mice [33].…”

Section: Discussionmentioning

confidence: 76%

“…One possibility is the engagement of MRTF-A which translocates to the nucleus in response to mechanical stress in a Rho kinase-dependent manner [39,40] and has also been shown to cause myofibroblast marker gene expression in cardiac fibroblasts [41]. Interestingly, RhoA activity (which in turn activates Rho kinase) is reduced in cardiac fibroblasts from syndecan-4 -/-mice [33]. Furthermore, NFATc4 over-expression resulted in increased MRTF-A mRNA, which may in turn promote myofibroblast differentiation [31].…”

Section: Discussionmentioning

confidence: 99%

Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress

Herum

Lunde

Skrbic

et al. 2013

Journal of Molecular and Cellular Cardiology

113

101

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“…108,109 Because of its anchoring to the cytoskeleton 110,111 and the ECM 112 it is believed to function as a mechanosensor. In the heart, syndecan-4 has been shown to be upregulated in disease 96,[113][114][115] and to mediate mechanical stress-induced remodeling. [114][115][116] …”

Section: 105mentioning

confidence: 99%

“…Due to the regulation of syndecan-4 during cardiac remodeling and inflammation 96,[113][114][115] , it is likely that syndecan-4 as a biomarker can provide information about the pathogenesis of heart failure, especially with regard to inflammation in the myocardium.…”

Section: 211mentioning

confidence: 99%

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

et al. 2013

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Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention. Syndecan‐4, a transmembrane heparan sulfate proteoglycan, is essential for pathological remodeling, and we here investigated its expression and shedding during heart failure. Pressure overload induced by aortic banding for 24 h and 1 week in mice increased syndecan‐4 mRNA, which correlated with mRNA of inflammatory cytokines. In cardiac myocytes and fibroblasts, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide through the toll‐like receptor‐4, induced syndecan‐4 mRNA. Bioinformatical and mutational analyses in HEK293 cells identified a functional site for the proinflammatory nuclear factor‐κB transcription factor in the syndecan‐4 promoter, and nuclear factor‐κB regulated syndecan‐4 mRNA in cardiac cells. Interestingly, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide induced nuclear factor‐κB‐dependent shedding of the syndecan‐4 ectodomain from cardiac cells. Overexpression of syndecan‐4 with mutated enzyme‐interacting domains suggested enzyme‐dependent heparan sulfate chains to regulate shedding. In cardiac fibroblasts, lipopolysaccharide reduced focal adhesion assembly, shown by immunohistochemistry, suggesting that inflammation‐induced shedding affects function. After aortic banding, a time‐dependent cardiac recruitment of T lymphocytes was observed by measuring CD3, CD4 and CD8 mRNA, which was reduced in syndecan‐4 knockout hearts. Finally, syndecan‐4 mRNA and shedding were upregulated in failing human hearts. Conclusively, our data suggest that syndecan‐4 plays an important role in the immune response of the heart to increased pressure, influencing cardiac remodeling and failure progression.

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Syndecan-4 Prevents Cardiac Rupture and Dysfunction After Myocardial Infarction

Abstract: These results suggest that Syn4 plays an important role in the inflammatory response and granulation tissue formation, thereby preventing cardiac rupture and dysfunction after MI.

Cited by 96 publications

References 52 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

Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

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