Opposing Actions of Fibroblast and Cardiomyocyte Smad3 Signaling in the Infarcted Myocardium

Kong, Ping; Shinde, Arti V.; Su, Ya; Russo, Ilaria; Chen, Bijun; Saxena, Amit; Conway, Simon J.; Graff, Jonathan M.; Frangogiannis, Nikolaos G.

doi:10.1161/circulationaha.117.029622

Cited by 146 publications

(140 citation statements)

References 51 publications

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“…In contrast, neither the myofibroblastic phenotype nor the survival of cardiomyocytes were negatively affected. The cell‐type–specific death effect triggered by sCD74/MIF co‐treatment is in accord with previous studies that reported that the same stimuli or pathways can induce opposing effects in cardiomyocytes and fibroblasts 61, 62. That sCD74/MIF co‐treatment does not induce de‐differentiation of myofibroblasts supports our assumption that it is unlikely that sCD74/MIF‐activated downstream pathways simultaneously affect the death and de‐differentiation of myofibroblasts.…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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“…Because the adult mammalian heart has negligible regenerative capacity, repair of the infarcted myocardium is dependent on fibroblast activation and subsequent formation of a collagen‐based scar. Perturbations in fibroblast activation and in the profile of ECM proteins in the infarcted and remodelling myocardium can be associated with increased dysfunction and adverse remodelling (Frangogiannis et al, ; Kong et al, ). During the proliferative phase of infarct healing, the cardiac fibroblast population markedly expands (Frangogiannis et al, ).…”

Section: Myofibroblast Activationmentioning

confidence: 99%

“…Design of effective therapeutic strategies requires understanding of the relative role of Smad‐dependent and Smad‐independent signalling in vivo (Bujak et al, ; Rainer et al, ). In the infarcted heart, experimental studies have suggested distinct effects of Smad‐dependent signalling in cardiomyocytes and fibroblasts (Kong et al, ). Moreover, non‐Smad pathways may also contribute to activation of interstitial cells towards a fibrogenic phenotype (Molkentin et al, ).…”

Section: Targeted Anti‐inflammatory Interventionsmentioning

confidence: 99%

Anti‐inflammatory therapies in myocardial infarction: failures, hopes and challenges

Huang

Frangogiannis

2018

British J Pharmacology

221

159

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In the infarcted heart, the damage-associated molecular pattern proteins released by necrotic cells trigger both myocardial and systemic inflammatory responses. Induction of chemokines and cytokines and up-regulation of endothelial adhesion molecules mediate leukocyte recruitment in the infarcted myocardium. Inflammatory cells clear the infarct of dead cells and matrix debris and activate repair by myofibroblasts and vascular cells, but may also contribute to adverse fibrotic remodelling of viable segments, accentuate cardiomyocyte apoptosis and exert arrhythmogenic actions. Excessive, prolonged and dysregulated inflammation has been implicated in the pathogenesis of complications and may be involved in the development of heart failure following infarction. Studies in animal models of myocardial infarction (MI) have suggested the effectiveness of pharmacological interventions targeting the inflammatory response. This article provides a brief overview of the cell biology of the post-infarction inflammatory response and discusses the use of pharmacological interventions targeting inflammation following infarction. Therapy with broad anti-inflammatory and immunomodulatory agents may also inhibit important repair pathways, thus exerting detrimental actions in patients with MI. Extensive experimental evidence suggests that targeting specific inflammatory signals, such as the complement cascade, chemokines, cytokines, proteases, selectins and leukocyte integrins, may hold promise. However, clinical translation has proved challenging. Targeting IL-1 may benefit patients with exaggerated post-MI inflammatory responses following infarction, not only by attenuating adverse remodelling but also by stabilizing the atherosclerotic plaque and by inhibiting arrhythmia generation. Identification of the therapeutic window for specific interventions and pathophysiological stratification of MI patients using inflammatory biomarkers and imaging strategies are critical for optimal therapeutic design. Abbreviations11β-HSD, 11-β hydroxysteroid dehydrogenase;

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“…As a main downstream signal transducer of TGF-β1, SMAD3 is the most critical YAP/TAZ target transcription factor which can be phosphorylated by TGF-β1 and then promotes expression of target genes including type I and type III collagen which are the primary component of the extracellular matrix [40,41]. Of note, a recent study reveals that myofibroblast-and cardiomyocytespecific activation of SMAD3 has contrasting functional outcomes in healing myocardial infarction [42]. erefore, in our study, whether the regulatory role of QSG is reflected in cardiomyocytes or fibroblasts remains to be explored in subsequent studies.…”

Section: Discussionmentioning

confidence: 99%

Antiapoptosis and Antifibrosis Effects of Qishen Granules on Heart Failure Rats via Hippo Pathway

Zhang

Liu

Gao

et al. 2019

BioMed Research International

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Qishen granules (QSG) are a famous formula with cardioprotective properties to heart failure (HF). The aim of this study was to investigate the underlying mechanism of QSG on apoptosis and fibrosis in the treatment of HF. HF model was induced by left anterior descending artery ligation on Sprague-Dawley rats. Transcriptome analysis was used to investigate the regulatory pathways of QSG on HF. Interestingly, downregulated genes of QSG were significantly enriched in Hippo pathway which plays a crucial role in regulating cell apoptosis and proliferation. We found that QSG inhibited the expressions of proapoptotic key proteins P-53 and fibrosis-related proteins TGF-β1, SMAD3, and CTGF. Further, we conducted research on the key proteins in the Hippo pathway upstream of CTGF and P-53. The results showed that MST1, P-MST1, P-LATS1, and RASSF1A that exert proapoptotic function were downregulated after QSG intervention. Similarly, P-YAP and P-TAZ, mediating self-degradation and apoptosis, were both observably decreased after QSG administration. Taken together, QSG are shown to be likely to exert cardioprotective effects by inhibiting the progression of apoptosis and fibrosis through Hippo pathway.

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Opposing Actions of Fibroblast and Cardiomyocyte Smad3 Signaling in the Infarcted Myocardium

Abstract: In healing myocardial infarction, myofibroblast- and cardiomyocyte-specific activation of Smad3 has contrasting functional outcomes that may involve activation of an integrin/reactive oxygen axis.

Cited by 146 publications

References 51 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

Anti‐inflammatory therapies in myocardial infarction: failures, hopes and challenges

Antiapoptosis and Antifibrosis Effects of Qishen Granules on Heart Failure Rats via Hippo Pathway

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