Syndecan-4 Is Essential for Development of Concentric Myocardial Hypertrophy via Stretch-Induced Activation of the Calcineurin-NFAT Pathway

Finsen, Alexandra Vanessa; Lunde, Ida G.; Sjaastad, Ivar; Østli, Even K.; Lyngra, Marianne; Jarstadmarken, Hilde; Hasic, Almira; Nygård, Ståle; Wilcox-Adelman, Sarah A.; Goetinck, Paul F.; Lyberg, Torstein; Skrbic, Biljana; Florholmen, Geir; Tønnessen, Theis; Louch, William E.; Djurovic, Srdjan; Carlson, Cathrine R.; Christensen, Geir

doi:10.1371/journal.pone.0028302

Cited by 68 publications

(130 citation statements)

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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%

“…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%

“…In our studies, we have developed a method for detection of syndecan-4 shedding from cells and in tissues by immunoblotting, using the calculated expected size of the shedding fragments and specific syndecan-4 antibodies that have been epitope mapped by us 114 with the methods described in this section is the dependence on antibodies, which will always raise questions regarding specificity. However, by using several and proper controls, we believe that we have demonstrated the validity of the aforementioned method to detect and quantify shedding of syndecan-4 by Western blotting.…”

Section: Western Blot Procedures For Detection Of Syndecan-4 Shedding mentioning

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%

“…114 Moreover, a recent study showed that the corresponding fragment arising from syncecan-1 shedding retained some of the function of full-length syndecan-1 in terms of intracellular signaling, and that shedding by ADAM17 in fact promoted migration. 198 In line with this, ADAMTS1-induced shedding of syndecan-4 was shown to reduce focal adhesions and promote migration of fibroblasts, thus resembling the phenotype of syndecan-4-deficient cells.…”

Section: The Multiple Roles Of Syndecan-4 In Cardiac Remodelingmentioning

confidence: 99%

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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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Section: 105mentioning

confidence: 99%

“…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%

Section: Western Blot Procedures For Detection Of Syndecan-4 Shedding mentioning

confidence: 99%

Section: 211mentioning

confidence: 99%

Section: The Multiple Roles Of Syndecan-4 In Cardiac Remodelingmentioning

confidence: 99%

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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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Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth

et al. 2013

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Background Ability of the heart to undergo pathological or physiological hypertrophy upon increased wall stress is critical for long-term compensatory function in response to increased workload demand. While substantial information has been published on the nature of the fundamental molecular signaling involved in hypertrophy, the role of extracellular matrix (ECM) protein Fibronectin (Fn) in hypertrophic signaling is unclear. Objective Delineate the role of Fn during pressure overload-induced pathological cardiac hypertrophy and physiological growth prompted by exercise. Methods and Results Genetic conditional ablation of Fn in adulthood blunts cardiomyocyte hypertrophy upon pressure overload via attenuated activation of Nuclear Factor of Activated T cells (NFAT). Loss of Fn delays development of heart failure and improves survival. In contrast, genetic deletion of Fn has no impact on physiological cardiac growth induced by voluntary wheel running. Down regulation of the transcription factor c/EBPβ (Ccaat-enhanced binding protein β), which is essential for induction of the physiological growth program, is unaffected by Fn deletion. Nuclear NFAT translocation is triggered by Fn in conjunction with up-regulation of the fetal gene program and hypertrophy of cardiomyocytes in vitro. Furthermore, activation of the physiological gene program induced by Insulin stimulation in vitro is attenuated by Fn, whereas Insulin had no impact on Fn-induced pathological growth program. Conclusion Fn contributes to pathological cardiomyocyte hypertrophy in vitro and in vivo via NFAT activation. Fn is dispensable for physiological growth in vivo, and Fn attenuates the activation of the physiological growth program in vitro.

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Syndecans in heart fibrosis

et al. 2016

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Heart disease is a deadly syndrome affecting millions worldwide. It reflects an unmet clinical need, and the disease mechanisms are poorly understood. Cardiac fibrosis is central to heart disease. The four-membered family of transmembrane proteoglycans, syndecan-1 to -4, is believed to regulate fibrosis. We review the current literature concerning syndecans in cardiac fibrosis. Syndecan expression is up-regulated in response to pro-inflammatory stimuli in various forms of heart disease with fibrosis. Mice lacking syndecan-1 and -4 show reduced activation of pro-fibrotic signaling and increased cardiac rupture upon infarction indicating an important role for these molecules. Whereas the short cytoplasmic tail of syndecans regulates signaling, their extracellular part, substituted with heparan sulfate glycosaminoglycan chains, binds a plethora of extracellular matrix (ECM) molecules involved in fibrosis, e.g., collagens, growth factors, cytokines, and immune cell adhesion proteins. Full-length syndecans induce pro-fibrotic signaling, increasing the expression of collagens, myofibroblast differentiation factors, ECM enzymes, growth factors, and immune cell adhesion molecules, thereby also increasing cardiac stiffness and preventing cardiac rupture. Upon pro-inflammatory stimuli, syndecan ectodomains are enzymatically released from heart cells (syndecan shedding). Shed ectodomains affect the expression of ECM molecules, promoting ECM degradation and cardiac rupture upon myocardial infarction. Blood levels of shed syndecan-1 and -4 ectodomains are associated with hospitalization, mortality, and heart remodeling in patients with heart failure. Improved understanding of syndecans and their modifying enzymes in cardiac fibrosis might contribute to the development of compounds with therapeutic potential, and enzymatically shed syndecan ectodomains might constitute a future prognostic tool for heart diseases with fibrosis. Graphical Abstract Graphical abstract summarizing the contents of the current review on syndecans in cardiac fibrosis. The heart is subjected to various forms of pathological stimuli, e.g., myocardial infarction, hypertension, valvular stenosis, infection, or an inherited genetic mutation, triggering responses in cells resident in the heart. Here, we focus on the responses of cardiac fibroblasts directing changes in the extracellular matrix resulting in cardiac fibrosis. A family of four transmembrane proteoglycans, syndecan-1 to -4, is expressed in the cell membrane of cardiac fibroblasts and is generally up-regulated in response to the above-mentioned pathological stimuli. Syndecans carry glycosaminoglycan chains on their extracellular domain, binding a plethora of molecules involved in fibrosis, e.g., growth factors, cytokines, immune cell adhesion proteins, and pathogens. Syndecans have a short cytoplasmic tail involved in pro-fibrotic signaling. The signaling and cellular processes governed by syndecans in the heart in response to pathological stimuli regulate important aspects of extracellular matr...

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Syndecan-4 Is Essential for Development of Concentric Myocardial Hypertrophy via Stretch-Induced Activation of the Calcineurin-NFAT Pathway

Cited by 68 publications

References 53 publications

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

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

Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth

Syndecans in heart fibrosis

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