Loss of Syndecan-1 Induces a Pro-inflammatory Phenotype in Endothelial Cells with a Dysregulated Response to Atheroprotective Flow

Voyvodic, Peter L.; Min, Daniel; Liu, Robert; Williams, Evan J.; Chitalia, Vipul C.; Dunn, Andrew K.; Baker, Aaron

doi:10.1074/jbc.m113.541573

Cited by 116 publications

(126 citation statements)

References 60 publications

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“…In addition, glycocalyx HSPGs are expressed at higher levels in vascular areas subjected to laminar shear stress, which is known to impart atherosclerosis resistance, than in regions of disturbed flow (43). Recent knockdown studies have indicated that both syndecan-1 and -4 HSPGs are critical in the flow-induced protection of ECs (44,45). In this light, signaling through the TMEM184A heparin receptor provides one mechanism by which HS levels would elicit cellular change during the development of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Transmembrane Protein 184A Is a Receptor Required for Vascular Smooth Muscle Cell Responses to Heparin

Pugh

Slee

Farwell³

et al. 2016

Journal of Biological Chemistry

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Vascular cell responses to exogenous heparin have been documented to include decreased vascular smooth muscle cell proliferation following decreased ERK pathway signaling. However, the molecular mechanism(s) by which heparin interacts with cells to induce those responses has remained unclear. Previously characterized monoclonal antibodies that block heparin binding to vascular cells have been found to mimic heparin effects. In this study, those antibodies were employed to isolate a heparin binding protein. MALDI mass spectrometry data provide evidence that the protein isolated is transmembrane protein 184A (TMEM184A). Commercial antibodies against three separate regions of the TMEM184A human protein were used to identify the TMEM184A protein in vascular smooth muscle cells and endothelial cells. A GFP-TMEM184A construct was employed to determine colocalization with heparin after endocytosis. Knockdown of TMEM184A eliminated the physiological responses to heparin, including effects on ERK pathway activity and BrdU incorporation. Isolated GFP-TMEM184A binds heparin, and overexpression results in additional heparin uptake. Together, these data support the identification of TMEM184A as a heparin receptor in vascular cells.For more than 30 years, heparin has been known to specifically bind to cells in the vasculature and alter their physiology in addition to its well recognized function as an anticoagulant. Heparin binds to many proteins, including numerous growth factors, cytokines, coagulation factors, cell adhesion molecules, growth factor receptors, matrix glycoproteins, and others (for a review, see Ref. 1). In fact, heparin and the closely related glycosaminoglycan heparan sulfate (HS), 4 interact with more than 400 proteins (2). Heparin decreases endothelial cell (EC) inflammatory gene expression and slows vascular smooth muscle cell (VSMC) proliferation (reviewed in Ref. 3). Specifically, ECs bind and endocytose heparin (4, 5), which is followed by decreased inflammatory signaling through NF-B (6) and stress kinase activity (7,8). Heparin binding in VSMCs (9) results in decreases in growth factor-induced ERK signaling (10, 11), inhibition of downstream transcription factor activity (12-14), changes in cell cycle inhibitory factors (15), and decreased proliferation (10, 16).Reports of fluorescent heparin uptake into cells, where it modulated transcription factor function (17), and the requirements of HSPGs for basic growth factor delivery to the nucleus (18) indicate that receptor-mediated uptake of heparin or HS may also be critical for some heparin effects. Similarly, shed HSPG syndecan-1 can be taken up by cells and transported to the nucleus, where it alters histone acetylation (19). HS chains are required for uptake, and this uptake can be inhibited by exogenously added heparin. It is likely that the uptake of highly charged heparin and HS chains involves a receptor to manage transport across the membrane. Although many heparin-interacting proteins have been linked to specific functions, a receptor respon...

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Section: Discussionmentioning

confidence: 99%

Transmembrane Protein 184A Is a Receptor Required for Vascular Smooth Muscle Cell Responses to Heparin

Pugh

Slee

Farwell³

et al. 2016

Journal of Biological Chemistry

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“…It is interesting that EC HSPGs are involved in EC remodeling in response to shear stress (51). In fact, knocking down synde-can-1 or -4 decreases the laminar shear stress protection of endothelial layers from inflammatory damage (52,53).…”

Section: Discussionmentioning

confidence: 99%

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

Farwell

Kanyi

Hamel

et al. 2016

Journal of Biological Chemistry

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Despite the large number of heparin and heparan sulfate binding proteins, the molecular mechanism(s) by which heparin alters vascular cell physiology is not well understood. Studies with vascular smooth muscle cells (VSMCs) indicate a role for induction of dual specificity phosphatase 1 (DUSP1) that decreases ERK activity and results in decreased cell proliferation, which depends on specific heparin binding. The hypothesis that unfractionated heparin functions to decrease inflammatory signal transduction in endothelial cells (ECs) through heparininduced expression of DUSP1 was tested. In addition, the expectation that the heparin response includes a decrease in cytokine-induced cytoskeletal changes was examined. Heparin pretreatment of ECs resulted in decreased TNF␣-induced JNK and p38 activity and downstream target phosphorylation, as identified through Western blotting and immunofluorescence microscopy. Through knockdown strategies, the importance of heparin-induced DUSP1 expression in these effects was confirmed. Quantitative fluorescence microscopy indicated that heparin treatment of ECs reduced TNF␣-induced increases in stress fibers. Monoclonal antibodies that mimic heparin-induced changes in VSMCs were employed to support the hypothesis that heparin was functioning through interactions with a receptor. Knockdown of transmembrane protein 184A (TMEM184A) confirmed its involvement in heparin-induced signaling as seen in VSMCs. Therefore, TMEM184A functions as a heparin receptor and mediates anti-inflammatory responses of ECs involving decreased JNK and p38 activity.For almost 100 years heparin has been used as an anticoagulant. Specific heparin interactions with proteins important in the anti-clotting system are now well understood. Many heparin binding proteins, including quite a few involved in modulating vascular function, inflammation, and angiogenesis, have been identified (reviewed in Ref. 1). The large number of reports indicating evidence of decreased endogenous heparin and heparan sulfates (HS) 3 in atherosclerosis (in model animals and human disease) led to a proposal that decreases in endogenous heparins might be important in the development of atherosclerosis (2). More recent evidence in support of that hypothesis includes increased heparanase expression in atherosclerosis (reviewed in Ref.3) and increased levels of glycocalyx heparan sulfate in regions of the vasculature where laminar flow decreases the likelihood of atherosclerosis development (4).In addition to heparin, heparin binding proteins typically also bind HS chains on HS proteoglycans (HSPGs). Although the carbohydrate backbones of heparin and HS are identical, modifications and sulfation patterns vary. HS chains have fewer sulfate residues per disaccharide and a lower overall charge, but their widespread expression suggests that HS may provide many in vivo functions identified originally as heparin functions (reviewed in Ref. 5). Heparin binding to growth factors modulates their activity and appears to protect them from degradation...

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“…Therefore, increased shedding of the syndecan-1 ectodomain by ADAM17 may aggravate the vascular phenotype in active AAV. 36 Membrane localization of ADAM17 is a prerequisite for its proper function. 37,38 Therefore, we speculated that ADAM17-specific activity in the blood samples of patients with AAV depends on its localization on cell-derived microparticles.…”

Section: Discussionmentioning

confidence: 99%

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

Bertram

Lovric

Engel

et al. 2015

Journal of the American Society of Nephrology

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ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasmaderived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.

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Loss of Syndecan-1 Induces a Pro-inflammatory Phenotype in Endothelial Cells with a Dysregulated Response to Atheroprotective Flow

Cited by 116 publications

References 60 publications

Transmembrane Protein 184A Is a Receptor Required for Vascular Smooth Muscle Cell Responses to Heparin

Transmembrane Protein 184A Is a Receptor Required for Vascular Smooth Muscle Cell Responses to Heparin

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

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