Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice

Summary The vascular endothelial surface is coated by the glycocalyx, a ubiquitous gel‐like layer composed of a membrane‐binding domain that contains proteoglycans, glycosaminoglycan side‐chains, and plasma proteins such as albumin and antithrombin. The endothelial glycocalyx plays a critical role in maintaining vascular homeostasis. However, this component is highly vulnerable to damage and is also difficult to examine. Recent advances in analytical techniques have enabled biochemical, visual and computational investigation of this vascular component. The glycocalyx modulates leukocyte–endothelial interactions, thrombus formation and other processes that lead to microcirculatory dysfunction and critical organ injury in sepsis. It also acts as a regulator of vascular permeability and contains mechanosensors as well as receptors for growth factors and anticoagulants. During the initial onset of sepsis, the glycocalyx is damaged and circulating levels of glycocalyx components, including syndecans, heparan sulfate and hyaluronic acid, can be measured and are reportedly useful as biomarkers for sepsis. Also, a new methodology using side‐stream dark‐field imaging is now clinically available for assessing the glycocalyx. Multiple factors including hypervolemia and hyperglycemia are toxic to the glycocalyx, and several agents have been proposed as therapeutic modalities, although no single treatment has been proven to be clinically effective. In this article, we review the derangement of the glycocalyx in sepsis. Despite the accumulated knowledge regarding the important roles of the glycocalyx, the relationship between derangement of the endothelial glycocalyx and severity of sepsis or disseminated intravascular coagulation has not been adequately elucidated and further work is needed.

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“…Strand et al . reported that the shedding of syndecan‐4 promotes leukocyte recruitment after a lipopolysaccharide challenge in mice.…”

Section: Evaluation Of Glycocalyx Damagementioning

confidence: 99%

“…Syndecan-4 is known as a binding site of antithrombin, and its derangement decreases the activity of antithrombin [47]. Strand et al [53] reported that the shedding of syndecan-4 promotes leukocyte recruitment after a lipopolysaccharide challenge in mice.…”

Section: Measurement Of Glycocalyx In Plasma and Urinementioning

confidence: 99%

Derangement of the endothelial glycocalyx in sepsis

Iba

Levy

2019

Journal of Thrombosis and Haemostasis

224

296

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“…Lumican, also a member of the SLRP family, induces pro-fibrotic signaling through activation of NFκB and is associated with increased cardiac fibrosis and development of heart failure in mice subjected to left ventricular pressure overload [104,105]. Moreover, the shed extracellular domain of the transmembrane proteoglycan syndecan-4 activates NFκB, and affects transcription of collagens and SMA in cultured cardiac fibroblasts [106]. Smaller fragments of the large extracellular carbohydrate chain hyaluronic acid (HA) have also been found to activate TLRs [107,108].…”

Section: Mechanical Activation Of Extracellular Matrix: a Vigilantmentioning

confidence: 99%

“…Cardiac fibroblasts in culture exposed to increased levels of shed syndecan-4 respond with altered expression of ECM genes [106], favoring ECM degradation. Cardiac fibroblasts treated with shed syndecan-4 fragments show reduced collagen I and III expression and reduced proliferation.…”

Section: Cell Surface Mechanotransduction: a Strained Relationshipmentioning

confidence: 99%

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

Herum

Lunde

McCulloch

et al. 2017

JCM

Self Cite

136

123

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Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression.

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“…The endothelial glycocalyx, a layer of negatively charged gel-like substance, exists on surfaces of pulmonary vascular endothelial cells. Heparan sulfate (HS) and syndecan-4 (SDC-4) are highly abundant in the glycocalyx [3,4]. The endothelial glycocalyx plays an important role in albumin exudation formation, leukocyte adhesion, and anticoagulation [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Crocin alleviates lipopolysaccharide-induced acute respiratory distress syndrome by protecting against glycocalyx damage and suppressing inflammatory signaling pathways

Zhang

Zhu

et al. 2020

Inflamm. Res.

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Objective To explore the mechanisms of crocin against glycocalyx damage and inflammatory injury in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) mice and LPS-stimulated human umbilical vein endothelial cells (HUVECs). Methods Mice were randomly divided into control, LPS, and crocin + LPS (15, 30, and 60 mg/kg) groups. HUVECs were separated into eight groups: control, crocin, matrix metalloproteinase 9 inhibitor (MMP-9 inhib), cathepsin L inhibitor (CTL inhib), LPS, MMP-9 inhib + LPS, CTL inhib + LPS, and crocin + LPS. The potential cytotoxic effect of crocin on HUVECs was mainly evaluated through methylthiazolyldiphenyl-tetrazolium bromide assay. Histological changes were assessed via hemotoxylin and eosin staining. Lung capillary permeability was detected on the basis of wet-dry ratio and through fluorescein isothiocyanate-albumin assay. Then, protein levels were detected through Western blot analysis, immunohistochemical staining, and immunofluorescence. Results This study showed that crocin can improve the pulmonary vascular permeability in mice with LPS-induced ARDS and inhibit the inflammatory signaling pathways of high mobility group box, nuclear factor κB, and mitogen-activated protein kinase in vivo and in vitro. Crocin also protected against the degradation of endothelial glycocalyx heparan sulfate and syndecan-4 by inhibiting the expressions of CTL, heparanase, and MMP-9 in vivo and in vitro. Overall, this study revealed the protective effects of crocin on LPS-induced ARDS and elaborated their underlying mechanism. Conclusion Crocin alleviated LPS-induced ARDS by protecting against glycocalyx damage and suppressing inflammatory signaling pathways.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice

Cited by 56 publications

References 49 publications

Derangement of the endothelial glycocalyx in sepsis

Derangement of the endothelial glycocalyx in sepsis

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

Crocin alleviates lipopolysaccharide-induced acute respiratory distress syndrome by protecting against glycocalyx damage and suppressing inflammatory signaling pathways

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