Heparin oligosaccharides enhance tissue-type plasminogen activator: a correlation between oligosaccharide length and stimulation of plasminogen activation

Jm, Edelberg; He, Conrad; Sv, Pizzo

doi:10.1021/bi00109a027

Cited by 12 publications

(5 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The activity of tPA has been shown to be enhanced by heparin (33). Indeed, increasing amounts of heparin enhanced necrotic chromatin degradation by Dnase1 ϩ/ϩ serum in a dose-dependent manner ( Figure 6B).…”

Section: Resultsmentioning

confidence: 91%

“…This is most likely explained by the fact that the plasminogen system is hyperactivated by heparin, which is known to stimulate the activity of tPA and thereby the activation of plasminogen (33). Therefore, the switch in the DNA cleavage pattern may be due to massive histone degradation, and not solely of histone H1, but also of nucleosome core histones, leading to the complete disintegration of the nucleosome.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Chromatin breakdown during necrosis by serum Dnase1 and the plasminogen system

Napirei¹,

Wulf²,

Mannherz³

2004

Arthritis & Rheumatism

115

120

View full text Add to dashboard Cite

Objective. Dnase1-deficient mice with the 129 ؋ C57BL/6 genetic background develop symptoms of systemic lupus erythematosus, such as high titers of antinuclear autoantibodies directed against nucleosomes. In this study we analyzed a potential molecular pathomechanism leading to this autoimmunity, by exploring the influence of extracellular Dnase1 present in serum on the breakdown of chromatin in necrotic cells in vitro.Methods. Human breast adenocarcinoma cells (MCF-7) and other cell lines were subjected to necrosis induced by hydrogen peroxide, streptolysin O, or freezethawing. Subsequently, the influence of sera from Dnase1-deficient and wild-type mice as well as the influence of purified enzymes present in the culture medium on the process of necrotic chromatin breakdown was investigated.Results. Necrotic chromatin breakdown resembled apoptotic DNA laddering and was catalyzed by serum Dnase1 in conjunction with plasmin. During necrosis, Dnase1 and plasminogen penetrated the cell and accumulated in the cytoplasm and nucleus. Plasminogen bound to the cytoskeleton and nuclear structures, was activated to plasmin by either tissue-type or urokinase-type plasminogen activator, and degraded histone H1, thereby facilitating internucleosomal DNA cleavage by Dnase1.Conclusion. Our results suggest that serum Dnase1 in cooperation with the plasminogen system guarantees a fast and effective breakdown of chromatin during necrosis by the combined cleavage of DNA as well as of DNA binding proteins. The failure of such a clearance mechanism might lead to antinuclear autoimmunity similar to that observed in the Dnase1-deficient mouse.

show abstract

Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Chromatin breakdown during necrosis by serum Dnase1 and the plasminogen system

Napirei¹,

Wulf²,

Mannherz³

2004

Arthritis & Rheumatism

115

120

View full text Add to dashboard Cite

show abstract

“…The most well documented examples are heparin stimulation of the inhibition of thrombin by antithrombin (52, 53) or by protein C inhibitor (54). Stimulation of activity has also been observed, as in the case of plasmin activation by plasminogen activators (55–57). Here we report the superstimulation of a proteinase enhancer by heparin (and heparan sulfate).…”

Section: Discussionmentioning

confidence: 96%

Role of the Netrin-like Domain of Procollagen C-Proteinase Enhancer-1 in the Control of Metalloproteinase Activity

Bekhouche

Kronenberg

Goff

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The netrin-like (NTR) domain is a feature of several extracellular proteins, most notably the N-terminal domain of tissue inhibitors of metalloproteinases (TIMPs), where it functions as a strong inhibitor of matrix metalloproteinases and some other members of the metzincin superfamily. The presence of a C-terminal NTR domain in procollagen C-proteinase enhancers (PCPEs), proteins that stimulate the activity of astacin-like tolloid proteinases, raises the possibility that this might also have inhibitory activity. Here we show that both long and short forms of the PCPE-1 NTR domain, the latter beginning at the N-terminal cysteine known to be critical for TIMP activity, show no inhibition, at micromolar concentrations, of several members of the metzincin superfamily, including matrix metalloproteinase-2, bone morphogenetic protein-1 (a tolloid proteinase), and different ADAMTS (a disintegrin and a metalloproteinase with thrombospondin motifs) proteinases from the adamalysin family. In contrast, we report that the NTR domain within PCPE-1 leads to superstimulation of bone morphogenetic protein-1 activity in the presence of heparin and heparan sulfate. These observations point to a new mechanism whereby binding to cell surface-associated or extracellular heparin-like sulfated glycosaminoglycans might provide a means to accelerate procollagen processing in specific cellular and extracellular microenvironments.

show abstract

“…In the latter study, heparin has been shown to enhance DNA degradation by serum in hydrogen peroxide-treated necrotic cells, but was not tested on purified oligo-nucleosomes. Actually, heparin also supports the activity of the plasminogen system (36), the activity of which is reduced in SLE, resulting in impaired fibrinolysis and potentially leading to thrombosis, a frequent lupus manifestation (37). Moreover, it is a DNase1-like 3 inhibitor (34).…”

Section: In Vitro Chromatin Degradation Is Dramatically Impaired In Smentioning

confidence: 99%

Deoxyribonuclease 1-Mediated Clearance of Circulating Chromatin Prevents From Immune Cell Activation and Pro-inflammatory Cytokine Production, a Phenomenon Amplified by Low Trap1 Activity: Consequences for Systemic Lupus Erythematosus

et al. 2021

View full text Add to dashboard Cite

Increased concentrations of circulating chromatin, especially oligo-nucleosomes, are observed in sepsis, cancer and some inflammatory autoimmune diseases like systemic lupus erythematosus (SLE). In SLE, circulating nucleosomes mainly result from increased apoptosis and decreased clearance of apoptotic cells. Once released, nucleosomes behave both as an autoantigen and as a damage-associated molecular pattern (DAMP) by activating several immune cells, especially pro-inflammatory cells. Deoxyribonuclease 1 (DNase1) is a major serum nuclease whose activity is decreased in mouse and human lupus. Likewise, the mitochondrial chaperone tumor necrosis factor (TNF) receptor-associated protein-1 (Trap1) protects against oxidative stress, which is increased in SLE. Here, using wild type, DNase1-deficient and DNase1/Trap1-deficient mice, we demonstrate that DNase1 is a major serum nuclease involved in chromatin degradation, especially when the plasminogen system is activated. In vitro degradation assays show that chromatin digestion is strongly impaired in serum from DNase1/Trap1-deficient mice as compared to wild type mice. In vivo, after injection of purified chromatin, clearance of circulating chromatin is delayed in DNase1/Trap1-deficient mice in comparison to wild type mice. Since defective chromatin clearance may lead to chromatin deposition in tissues and subsequent immune cell activation, spleen cells were stimulated in vitro with chromatin. Splenocytes were activated by chromatin, as shown by interleukin (IL)-12 secretion and CD69 up-regulation. Moreover, cell activation was exacerbated when Trap1 is deficient. Importantly, we also show that cytokines involved in lupus pathogenesis down-regulate Trap1 expression in splenocytes. Therefore, combined low activities of both DNase1 and Trap1 lead to an impaired degradation of chromatin in vitro, delayed chromatin clearance in vivo and enhanced activation of immune cells. This situation may be encountered especially, but not exclusively, in SLE by the negative action of cytokines on Trap1 expression.

show abstract

Heparin oligosaccharides enhance tissue-type plasminogen activator: a correlation between oligosaccharide length and stimulation of plasminogen activation

Cited by 12 publications

References 30 publications

Chromatin breakdown during necrosis by serum Dnase1 and the plasminogen system

Chromatin breakdown during necrosis by serum Dnase1 and the plasminogen system

Role of the Netrin-like Domain of Procollagen C-Proteinase Enhancer-1 in the Control of Metalloproteinase Activity

Deoxyribonuclease 1-Mediated Clearance of Circulating Chromatin Prevents From Immune Cell Activation and Pro-inflammatory Cytokine Production, a Phenomenon Amplified by Low Trap1 Activity: Consequences for Systemic Lupus Erythematosus

Contact Info

Product

Resources

About