Heparin treatment of vascular smooth muscle cells results in the synthesis of the dual‐specificity phosphatase MKP‐1

Blaukovitch, Cheryl Isleib; Pugh, Raymond; Gilotti, Albert C.; Kanyi, Daniela; Lowe-Krentz, Linda J.

doi:10.1002/jcb.22543

Cited by 12 publications

(31 citation statements)

References 48 publications

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“…4, E and F). Therefore, heparin effects on JNK and p38 activation require the induction of DUSP1 in a manner similar to VSMCs (24).…”

Section: Dusp1 Is Critical For Heparin-induced Decreases In Jnk and P38mentioning

confidence: 99%

“…Activity-In VSMCs, heparin has been shown to induce concentration-and time-dependent expression of DUSP1, a dual-specificity phosphatase that localizes to the nucleus, where it regulates MAPK signaling (24). To test the hypothesis that increased DUSP1 is required for heparin-induced decreases in JNK and p38 activation, we first evaluated whether increased DUSP1 is observed in heparin-treated ECs (Fig.…”

Section: Dusp1 Is Critical For Heparin-induced Decreases In Jnk and P38mentioning

confidence: 99%

“…In support of this idea, DUSP1 induction by anti-inflammatory glucocorticoid hormones does increase DUSP1 expression (25,26), and low molecular weight heparin has been reported to decrease peroxide-induced JNK and p38 activity (27). Heparin uptake and many heparin functions likely depend on a heparin/HS receptor.Monoclonal antibodies that block heparin binding to endothelial cells (HRmAbs) are able to mimic heparin responses in VSMCs (10,19,22,24), providing evidence that the protein to which they bind functions as a heparin receptor. The accompanying report identifies TMEM184A as the heparin-interacting protein to which the HRmAbs bind (28).…”

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confidence: 99%

“…These responses include decreases in cell proliferation (18,19), ERK pathway activity (19 -21), and activation of specific transcription factors (21)(22)(23). Heparin binding results in increased levels of DUSP1 protein that are required for decreases in ERK activity (24). The heparin-induced increases in VSMC DUSP1 suggest that heparin-induced decreases in EC inflammatory responses might also involve DUSP1 expression.…”

mentioning

confidence: 99%

“…Monoclonal antibodies that block heparin binding to endothelial cells (HRmAbs) are able to mimic heparin responses in VSMCs (10,19,22,24), providing evidence that the protein to which they bind functions as a heparin receptor. The accompanying report identifies TMEM184A as the heparin-interacting protein to which the HRmAbs bind (28).…”

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confidence: 99%

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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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“…4, E and F). Therefore, heparin effects on JNK and p38 activation require the induction of DUSP1 in a manner similar to VSMCs (24).…”

Section: Dusp1 Is Critical For Heparin-induced Decreases In Jnk and P38mentioning

confidence: 99%

Section: Dusp1 Is Critical For Heparin-induced Decreases In Jnk and P38mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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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Heparin Responses in Vascular Smooth Muscle Cells Involve cGMP‐Dependent Protein Kinase (PKG)

Gilotti

Nimlamool

Pugh

et al. 2014

Journal Cellular Physiology

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Published data provide strong evidence that heparin treatment of proliferating vascular smooth muscle cells results in decreased signaling through the ERK pathway and decreases in cell proliferation. In addition, these changes have been shown to be mimicked by antibodies that block heparin binding to the cell surface. Here we provide evidence that the activity of protein kinase G is required for these heparin effects. Specifically, a chemical inhibitor of protein kinase G, Rp-8-pCPT-cGMS, eliminates heparin and anti-heparin receptor antibody effects on bromodeoxyuridine incorporation into growth factor stimulated cells. In addition, protein kinase G inhibitors decrease heparin effects on ERK activity, phosphorylation of the transcription factor ELK-1, and heparin induced MKP-1 synthesis. Although transient, the levels of cGMP increase in heparin treated cells. Finally, knock down of protein kinase G also significantly decreases heparin effects in growth factor activated vascular smooth muscle cells. Together, these data indicate that heparin effects on vascular smooth muscle cell proliferation depend, at least in part, on signaling through protein kinase G.

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Enhancing angiogenesis alleviates hypoxia and improves engraftment of enteric cells in polycaprolactone scaffolds

Singh

Dunn

2012

J Tissue Eng Regen Med

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We examined whether expediting angiogenesis in porous polycaprolactone (PCL) scaffolds could reduce hypoxia and consequently improve the survival of transplanted enteric cells. To accelerate angiogenesis, we delivered vascular endothelial growth factor (VEGF) using PCL scaffolds with surface cross-linked heparin. The scaffold fabrication and characterization has been reported in our previous study. Enteric cells, isolated from intestinal tissue of neonatal mice and expanded in vitro for 10 days, exhibited high expression levels for contractile protein alpha-smooth muscle actin and desmin. The cultured enteric cells were seeded in scaffolds and were implanted subcutaneously in immunodeficient mice for 7 and 14 days. At day 7, the heparin-modified PCL scaffolds with VEGF exhibited significantly increased angiogenesis and engraftment of enteric cells, with a simultaneous reduction in hypoxia. At day 14, the blood vessels grew across the entire thickness of the scaffold and resulted in significantly diminished hypoxic environment; however, the transplanted cell density did not increase further. In conclusion, the enhancement of angiogenesis reduced cellular hypoxia and improved engraftment of enteric cells.

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Heparin treatment of vascular smooth muscle cells results in the synthesis of the dual‐specificity phosphatase MKP‐1

Cited by 12 publications

References 48 publications

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

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

Heparin Responses in Vascular Smooth Muscle Cells Involve cGMP‐Dependent Protein Kinase (PKG)

Enhancing angiogenesis alleviates hypoxia and improves engraftment of enteric cells in polycaprolactone scaffolds

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