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Robert W. Colman - One of the best experts on this subject based on the ideXlab platform.
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an essential role of high molecular weight Kininogen in endotoxemia
Journal of Experimental Medicine, 2017Co-Authors: Aizhen Yang, Robert W. Colman, Zhanli Xie, Bo Wang, Jihong DaiAbstract:In this study, we show that mice lacking High-Molecular-Weight Kininogen (HK) were resistant to lipopolysaccharide (LPS)-induced mortality and had significantly reduced circulating LPS levels. Replenishment of HK-deficient mice with human HK recovered the LPS levels and rendered the mice susceptible to LPS-induced mortality. Binding of HK to LPS occurred through the O-polysaccharide/core oligosaccharide, consistent with the ability to bind LPS from K. pneumoniae, P. aeruginosa, S. minnesota, and different E. coli strains. Binding of LPS induced plasma HK cleavage to the two-chain form (HKa, containing a heavy chain [HC] and a light chain [LC]) and bradykinin. Both HKa and the LC, but not the HC, could disaggregate LPS. The light chain bound LPS with high affinity (K d = 1.52 × 10-9 M) through a binding site in domain 5 (DHG15). A monoclonal antibody against D5 significantly reduced LPS-induced mortality and circulating LPS levels in wild-type mice. Thus, HK, as a major LPS carrier in circulation, plays an essential role in endotoxemia.
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cleaved high molecular weight Kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway
Oncogene, 2009Co-Authors: Yuchuan Liu, Robin A Pixley, Mario Fusaro, Gustavo Godoy, Erin Kim, Michael Bromberg, Robert W. ColmanAbstract:Cleaved High-Molecular-Weight Kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway
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inhibition of tumor angiogenesis in vivo by a monoclonal antibody targeted to domain 5 of high molecular weight Kininogen
Blood, 2004Co-Authors: James S Song, Harlan N. Bradford, Robin A Pixley, Irma Isordiasalas, Irma M Sainz, Stephen C Cosenza, Abdel Bior, Yanlin Guo, Premkumar E Reddy, Robert W. ColmanAbstract:We have shown that human high molecular weight Kininogen is proangiogenic due to release of bradykinin. We now determined the ability of a murine monoclonal antibody to the light chain of high molecular weight Kininogen, C11C1, to inhibit tumor growth compared to isotype-matched murine IgG. Monoclonal antibody C11C1 efficiently blocks binding of high molecular weight Kininogen to endothelial cells in a concentration-dependent manner. The antibody significantly inhibited growth of human colon carcinoma cells in a nude mouse xenograft assay and was accompanied by a significant reduction in the mean microvascular density compared to the IgG control group. We also showed that a hybridoma producing monoclonal antibody C11C1 injected intramuscularly exhibited markedly smaller tumor mass in a syngeneic host compared to a hybridoma producing a monoclonal antibody to the high molecular weight Kininogen heavy chain or to an unrelated plasma protein. In addition, tumor inhibition by purified monoclonal antibody C11C1 was not due to direct antitumor effect because there was no decrease of tumor cell growth in vitro in contrast to the in vivo inhibition. Our results indicate that monoclonal antibody C11C1 inhibits angiogenesis and human tumor cell growth in vivo and has therapeutic potential for treatment of human cancer. (Blood. 2004;104:2065-2072)
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The role of plasma high molecular weight Kininogen in experimental intestinal and systemic inflammation
Archives of medical research, 2004Co-Authors: Irma Isordia-salas, Irma M Sainz, Robin A Pixley, Carlos Martínez-murillo, Robert W. ColmanAbstract:Inflammation is accompanied by activation of the plasma kallikrein-kinin system (KKS). KKS activation has been demonstrated in a variety of inflammatory human diseases. To further explore the participation of KKS in arthritis and inflammatory bowel disease, we used two experimental animal models in arthritis and enterocolitis. We found that activation of KKS is associated with arthritis induced by intraperitoneal injection of peptidoglycan-polysaccharide polymers (PG-PS) as well as the enterocolitis and systemic inflammation induced also by PG-PS when injected into the intestinal wall of genetically susceptible Lewis rats. We postulated that KKS participates in the pathogenesis of inflammatory reactions involved in cellular injury, coagulation, fibrinolysis, kinin formation, complement activation, cytokine secretion, and release of proteases. We demonstrated that therapy with a specific plasma kallikrein inhibitor modulated the experimental enterocolitis, arthritis, and systemic inflammation. The fact that deficiency of plasma high molecular weight Kininogen in the genetically susceptible Lewis rat results in decreased chronic enterocolitis and systemic inflammation also supports our hypothesis. We suggest that KKS plays a similar role in idiopathic human intestinal inflammatory disease and arthritis, making kallikrein-kinin system proteins appealing targets for drug therapy in chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease.
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Upregulation of Cdc2 and cyclin A during apoptosis of endothelial cells induced by cleaved High-Molecular-Weight Kininogen.
American journal of physiology. Heart and circulatory physiology, 2003Co-Authors: Shujie Wang, Robert W. Colman, Irma Isordia-salas, Muneer G. Hasham, Alexander Y. Tsygankov, Yanlin GuoAbstract:We (8) reported that the cleaved High-Molecular-Weight Kininogen (HKa) and its domain 5 (D5) inhibited angiogenesis. Further studies (15) revealed that D5 could inhibit cell proliferation and induc...
Robin A Pixley - One of the best experts on this subject based on the ideXlab platform.
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cleaved high molecular weight Kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway
Oncogene, 2009Co-Authors: Yuchuan Liu, Robin A Pixley, Mario Fusaro, Gustavo Godoy, Erin Kim, Michael Bromberg, Robert W. ColmanAbstract:Cleaved High-Molecular-Weight Kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway
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inhibition of tumor angiogenesis in vivo by a monoclonal antibody targeted to domain 5 of high molecular weight Kininogen
Blood, 2004Co-Authors: James S Song, Harlan N. Bradford, Robin A Pixley, Irma Isordiasalas, Irma M Sainz, Stephen C Cosenza, Abdel Bior, Yanlin Guo, Premkumar E Reddy, Robert W. ColmanAbstract:We have shown that human high molecular weight Kininogen is proangiogenic due to release of bradykinin. We now determined the ability of a murine monoclonal antibody to the light chain of high molecular weight Kininogen, C11C1, to inhibit tumor growth compared to isotype-matched murine IgG. Monoclonal antibody C11C1 efficiently blocks binding of high molecular weight Kininogen to endothelial cells in a concentration-dependent manner. The antibody significantly inhibited growth of human colon carcinoma cells in a nude mouse xenograft assay and was accompanied by a significant reduction in the mean microvascular density compared to the IgG control group. We also showed that a hybridoma producing monoclonal antibody C11C1 injected intramuscularly exhibited markedly smaller tumor mass in a syngeneic host compared to a hybridoma producing a monoclonal antibody to the high molecular weight Kininogen heavy chain or to an unrelated plasma protein. In addition, tumor inhibition by purified monoclonal antibody C11C1 was not due to direct antitumor effect because there was no decrease of tumor cell growth in vitro in contrast to the in vivo inhibition. Our results indicate that monoclonal antibody C11C1 inhibits angiogenesis and human tumor cell growth in vivo and has therapeutic potential for treatment of human cancer. (Blood. 2004;104:2065-2072)
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A Monoclonal Antibody to High-Molecular Weight Kininogen Is Therapeutic in a Rodent Model of Reactive Arthritis
The American journal of pathology, 2004Co-Authors: Ricardo G. Espinola, Robin A Pixley, Irma M Sainz, Audrey B. Uknis, Irma Isordia-salas, Raul A. Dela Cadena, Walter K. Long, Alexis Agelan, John P. Gaughan, Albert AdamAbstract:We reported that high-molecular weight Kininogen is proangiogenic by releasing bradykinin and that a monoclonal antibody to high-molecular weight Kininogen, C11C1, blocked its binding to endothelial cells. We now test if this antibody can prevent arthritis and systemic inflammation in a Lewis rat model. We studied 32 animals for 16 days. Group I (negative control) received saline intraperitoneally. Group II (disease-treated) received peptidoglycan-polysaccharide simultaneously with C11C1. Group III (disease-untreated) received peptidoglycan-polysaccharide simultaneously with isotype-matched mouse IgG. Group IV (disease-free-treated) and group V (disease-free isotype-treated) received saline and C11C1 or mouse IgG. Analysis of joint diameter changes showed a decrease in the C11C1 disease-treated group compared to the disease-untreated group. The hind paw inflammatory score showed a decrease in the intensity and extent of inflammation between the disease-untreated and the C11C1 disease-treated group. Prekallikrein, high-molecular weight Kininogen, factor XI, and factor XII were decreased in the disease-untreated group compared to the C11C1 disease-treated group. T-Kininogen was increased in the disease-untreated group when compared with the C11C1 disease-treated group. Disease-free groups IV and V did not show any sign of inflammation at any time. This study shows that monoclonal antibody C11C1 attenuates plasma kallikrein-kinin system activation, local and systemic inflammation, indicating therapeutic potential in reactive arthritis.
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The role of plasma high molecular weight Kininogen in experimental intestinal and systemic inflammation
Archives of medical research, 2004Co-Authors: Irma Isordia-salas, Irma M Sainz, Robin A Pixley, Carlos Martínez-murillo, Robert W. ColmanAbstract:Inflammation is accompanied by activation of the plasma kallikrein-kinin system (KKS). KKS activation has been demonstrated in a variety of inflammatory human diseases. To further explore the participation of KKS in arthritis and inflammatory bowel disease, we used two experimental animal models in arthritis and enterocolitis. We found that activation of KKS is associated with arthritis induced by intraperitoneal injection of peptidoglycan-polysaccharide polymers (PG-PS) as well as the enterocolitis and systemic inflammation induced also by PG-PS when injected into the intestinal wall of genetically susceptible Lewis rats. We postulated that KKS participates in the pathogenesis of inflammatory reactions involved in cellular injury, coagulation, fibrinolysis, kinin formation, complement activation, cytokine secretion, and release of proteases. We demonstrated that therapy with a specific plasma kallikrein inhibitor modulated the experimental enterocolitis, arthritis, and systemic inflammation. The fact that deficiency of plasma high molecular weight Kininogen in the genetically susceptible Lewis rat results in decreased chronic enterocolitis and systemic inflammation also supports our hypothesis. We suggest that KKS plays a similar role in idiopathic human intestinal inflammatory disease and arthritis, making kallikrein-kinin system proteins appealing targets for drug therapy in chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease.
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inhibition of angiogenesis by antibody blocking the action of proangiogenic high molecular weight Kininogen
Journal of Thrombosis and Haemostasis, 2003Co-Authors: Robert W. Colman, Robin A Pixley, Irma Isordiasalas, James S Song, Irma M Sainz, S N Muhamed, J A Powell, Shaker A MousaAbstract:Previously we demonstrated that domain 5 (D5) of High-Molecular-Weight Kininogen (HK) inhibits neovascularization in the chicken chorioallantoic membrane (CAM) assay and further found that kallikrein cleaved HK (HKa) inhibited FGF2-and VEGF-induced neovascularization, and thus was antiangiogenic. In this study, we sought to demonstrate whether uncleaved HK stimulates neovascularization and thus is proangiogenic. The chick chorioallantoic membrane was used as an in ovo assay of angiogenesis. Low-molecular-weight Kininogen stimulates angiogenesis, indicating that D5 is not involved. Bradykinin stimulates neovascularization equally to HK and LK and is likely to be responsible for the effect of HK. A murine monoclonal antibody to HK (C11C1) also recognizes a similar component in chicken plasma as detected by surface plasmon resonance. Angiogenesis induced by FGF2 and VEGF is inhibited by this monoclonal antibody and is a more potent inhibitor of neovascularization induced by VEGF than an integrin alphavbeta3 antibody (LM 609). Our postulate that C11C1 inhibits the stimulation of angiogenesis by HK was confirmed when either C11C1 or D5 completely inhibited angiogenesis in the CAM induced by HK. Growth of human fibrosarcoma (HT-1080) on the CAM was inhibited by GST-D5 and C11C1. These results indicate HK is proangiogenic probably by releasing bradykinin and that a monoclonal antibody directed to HK could serve as an antiangiogenic agent with a potential for inhibiting tumor angiogenesis and other angiogenesis-mediated disorders.
Keith R. Mccrae - One of the best experts on this subject based on the ideXlab platform.
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Endothelial-cell apoptosis induced by cleaved High-Molecular-Weight Kininogen (HKa) is matrix dependent and requires the generation of reactive oxygen species
Blood, 2006Co-Authors: Danyu Sun, Keith R. MccraeAbstract:High–molecular-weight Kininogen (HK) is an abundant plasma protein that plays a central role in activation of the kallikrein-kinin system. Cleavage of HK by plasma kallikrein results in release of the nonapeptide bradykinin (BK), leaving behind cleaved high–molecular-weight Kininogen (HKa). Previous studies have demonstrated that HKa induces apoptosis of proliferating endothelial cells and inhibits angiogenesis in vivo, activities mediated primarily through its domain 5. However, the mechanisms by which these effects occur are not well understood. Here, we demonstrate that HKa induces apoptosis of endothelial cells cultured on gelatin, vitronectin, fibronectin, or laminin but not collagen type I or IV. The ability of HKa to induce endothelial-cell apoptosis is dependent on the generation of intracellular reactive oxygen species and associated with depletion of glutathione and peroxidation of endothelial-cell lipids, effects that occur only in cells cultured on matrix proteins permissive for HKa-induced apoptosis. Finally, the ability of HKa to induce endothelial-cell apoptosis is blocked by the addition of reduced glutathione or N-acetylcysteine. These studies demonstrate a unique role for oxidant stress in mediating the activity of an antiangiogenic polypeptide and highlight the importance of the extracellular matrix in regulating endothelial-cell survival.
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Inhibition of angiogenesis by cleaved high molecular weight Kininogen (HKa) and HKa domain 5.
Current cancer drug targets, 2005Co-Authors: Keith R. Mccrae, Fernando Donaté, Sergei Merkulov, Danyu Sun, David E. ShawAbstract:High molecular weight Kininogen (HK) is an abundant, multi-domain plasma protein that circulates in plasma primarily in its single chain form. Proteolytic cleavage of HK by plasma kallikrein releases the vasoactive nanopeptide bradykinin (BK), and converts HK into two-chain HK (HKa). BK appears to have pro-angiogenic activity, most likely mediated through binding to B1 and B2 receptors on endothelial cells. Conversely, HKa and its domain 5, but not (single chain) HK, have potent anti-angiogenic activity comparable to other endogenous angiogenesis inhibitors. The mechanism by which HKa exerts its anti-angiogenic activity remains controversial, but appears to involve binding to cell surface tropomyosin and induction of apoptosis of proliferating endothelial cells. A role for tropomyosin in mediating the anti-angiogenic signals of other anti-angiogenic proteins such as endostatin and histidine-proline-rich glycoprotein (HPRG) has also been reported. Here we review the physiological importance of high molecular weight Kininogen in angiogenesis, with emphasis on the mechanism(s) by which this activity is mediated.
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Inhibition of angiogenesis by two-chain high molecular weight Kininogen (HKa) and Kininogen-derived polypeptides.
Canadian journal of physiology and pharmacology, 2002Co-Authors: Jing Chuan Zhang, Jose Juarez, Marian L. Plunkett, Fernando Donaté, Ramasamy Sakthivel, Andrew P. Mazar, Keith R. MccraeAbstract:We recently reported that the two-chain form of human high molecular weight Kininogen (HKa) inhibits angiogenesis by inducing endothelial cell apoptosis (Zhang et al. 2000). This property appears t...
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Inhibition of angiogenesis by two-chain high molecular weight Kininogen (HKa) and Kininogen-
2002Co-Authors: Jing Chuan Zhang, Marian L. Plunkett, Ramasamy Sakthivel, Andrew P. Mazar, Keith R. MccraeAbstract:We recently reported that the two-chain form of human high molecular weight Kininogen (HKa) inhibits angiogenesis by inducing endothelial cell apoptosis (Zhang et al. 2000). This property appears to be primarily con - ferred by HKa domain 5 (HKa D5). In this manuscript, we further characterize the activity of these polypeptides to- ward proliferating endothelial cells, as well as their in vivo anti-angiogenic activity in the chick chorioallantoic membrane (CAM). We also demonstrate that short peptides derived from endothelial cell binding regions in HKa do- mains 3 and 5 inhibit endothelial cell proliferation and induce endothelial cell apoptosis. Like HKa and HKa D5, pep- tides derived from the latter domain induce endothelial cell apoptosis in a Zn 2+ -dependent manner, while those derived from domain 3 function independently of Zn 2+ . The implications of these findings to the regulation of angiogenesis and
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two chain high molecular weight Kininogen induces endothelial cell apoptosis and inhibits angiogenesis partial activity within domain 5
The FASEB Journal, 2000Co-Authors: Jing Chuan Zhang, Ramasamy Sakthivel, David E. Shaw, Kevin P Claffey, Zbigniev Darzynkiewicz, Juan Fernando Martinez Leal, Yichun Wang, Keith R. MccraeAbstract:We previously reported that the binding of two-chain high molecular weight Kininogen (HKa) to endothelial cells may occur through interactions with endothelial urokinase receptors. Since the binding of urokinase to urokinase receptors activates signaling responses and may stimulate mitogenesis, we assessed the effect of HKa binding on endothelial cell proliferation. Unexpectedly, HKa inhibited proliferation in response to several growth factors, with 50% inhibition caused by approximately 10 nM HKa. This activity was Zn(2+) dependent and not shared by either single-chain high molecular weight Kininogen (HK) or low molecular weight Kininogen. HKa selectively inhibited the proliferation of human umbilical vein and dermal microvascular endothelial cells, but did not affect that of umbilical vein or human aortic smooth muscle cells, trophoblasts, fibroblasts, or carcinoma cells. Inhibition of endothelial proliferation by HKa was associated with endothelial cell apoptosis and unaffected by antibodies that block the binding of HK or HKa to any of their known endothelial receptors. Recombinant HK domain 5 displayed activity similar to that of HKa. In vivo, HKa inhibited neovascularization of subcutaneously implanted Matrigel plugs, as well as rat corneal angiogenesis. These results demonstrate that HKa is a novel inhibitor of angiogenesis, whose activity is dependent on the unique conformation of the two-chain molecule.
Allen P. Kaplan - One of the best experts on this subject based on the ideXlab platform.
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interaction of high molecular weight Kininogen binding proteins on endothelial cells
Thrombosis and Haemostasis, 2003Co-Authors: Kusumam Joseph, Baby G Tholanikunnel, Berhane Ghebrehiwet, Allen P. KaplanAbstract:Cell surface proteins reported to participate in the binding and activation of the plasma kinin-forming cascade includes gC1qR, cytokeratin 1 and u-PAR. Each of these proteins binds high molecular weight Kininogen (HK) as well as Factor XII. The studies on the interaction of these proteins, using dot-blot analysis, revealed that cytokeratin 1 binds to both gC1qR and u-PAR while gC1qR and u-PAR do not bind to each other. The binding properties of these proteins were further analyzed by gel filtration. When biotinylated cytokeratin 1 was incubated with either gC1qR or u-PAR and gel filtered, a new, higher molecular weight peak containing biotin was observed indicating complex formation.The protein shift was also similar to the biotin shift. Further, immunoprecipitation of solubilized endo-thelial cell plasma membrane proteins with anti-gC1qR recovered both gC1qR and cytokeratin 1, but not u-PAR. Immunoprecipitation with anti-u-PAR recovered only u-PAR and cytokeratin 1. By competitive ELISA, gC1qR inhibits u-PAR from binding to cytokeratin 1; u-PAR inhibits gC1qR binding to a lesser extent and requires a 10-fold molar excess. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular complexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored.
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Assessment of the role of heparan sulfate in high molecular weight Kininogen binding to human umbilical vein endothelial cells
Journal of thrombosis and haemostasis : JTH, 2003Co-Authors: Lawrence P. Fernando, A.n. Fernando, Kusumam Joseph, Allen P. KaplanAbstract:Summary. The assembly and activation of the kinin forming system components on human umbilical vein endothelial cells (HUVEC) have been studied in great detail. Proteins such as gC1qR, cytokeratin-1 and u-PAR have been identified to be responsible for Zn2+-dependent binding of high molecular weight Kininogen (HK) to HUVEC. Heparan sulfate has also been shown to have a major role in Zn2+-dependent binding of HK to the endothelial cell line, Ea.hy 926. In this study, we have analyzed the possible contribution of heparan sulfate to high molecular weight Kininogen binding to HUVEC using multiple approaches. The presence of heparan sulfate on HUVEC was analyzed by staining with an antibody specific for heparan sulfate. Incubation of the cells with bacterial heparinases removed the heparan sulfate from the cell surface to the level seen with a control antibody, however, the Zn2+-dependent binding of HK was not affected. Further, blocking of heparan sulfate with a specific antibody to heparan sulfate even after digestion with heparinases did not reduce HK binding whereas antibodies to the proteins gC1qR and cytokeratin-1 consistently reduced the binding of HK to the endothelial cells. The binding intensities of FITC-labeled HK were similar in heparinase-treated and -untreated HUVEC. The rate of kallikrein formation by the assembly of factor XII, HK and PK were similar in both heparinase-treated and non-treated HUVEC. All of these data indicate that heparan sulfate does not contribute significantly to HK binding to HUVEC.
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cytokeratin 1 and gc1qr mediate high molecular weight Kininogen binding to endothelial cells
Clinical Immunology, 1999Co-Authors: Kusumam Joseph, Berhane Ghebrehiwet, Allen P. KaplanAbstract:High molecular weight Kininogen (HK) attaches to endothelial cells by separate sites on the heavy and light chains and requires 15-50 microM zinc. Previously identified binding proteins include gC1qR, cytokeratin 1, and the urokinase plasminogen activator receptor; however, their relative contributions to binding are not yet clarified. We have prepared affinity columns to which were coupled either cleaved HK or peptide LDCNAEVYVVPWEKKIYPTVNCQPLGM derived from heavy-chain domain 3. Endothelial cell membranes were solubilized and chromatographed in the presence or absence of zinc ion, the bound proteins were eluted, and active fractions were identified by dot blot using biotinylated HK, SDS/PAGE, and Western blot analysis. The peptide containing column eluate revealed but one band at 68 kDa if zinc ion was present which was identified as cytokeratin 1 by amino acid sequencing of an internal peptide. The HK affinity column revealed bands at 68 kDa (cytokeratin 1), 33 kDa (gC1qR), and 66 kDa (unidentified). HK or domain 3-derived peptide bound to the 68 kDa band; prekallikrein and Factor XII did not. HK or Factor XII bound to the 33-kDa band if zinc was present while no binding to the 66 kDa band was observed. Antibody to cytokeratin 1 inhibited HK binding to endothelial cells by 30%, antibody to gC1qR inhibited HK binding to endothelial cells by 72%, and a mixture of both inhibited binding by 86%. Our data suggest HK binding by interaction of the heavy-chain domain 3 with cytokeratin 1 and the light chain with gC1qR.
Yanlin Guo - One of the best experts on this subject based on the ideXlab platform.
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two faces of high molecular weight Kininogen hk in angiogenesis bradykinin turns it on and cleaved hk hka turns it off
Journal of Thrombosis and Haemostasis, 2005Co-Authors: Yanlin Guo, R W ColmanAbstract:Summary. High-Molecular-Weight Kininogen (HK) is a plasma protein that possesses multiple physiological functions. Originally identified as a precursor of bradykinin, a bioactive peptide that regulates many cardiovascular processes, it is now recognized that HK plays important roles in fibrinolysis, thrombosis, and inflammation. HK binds to endothelial cells where it can be cleaved by plasma kallikrein to release bradykinin (BK). The remaining portion of the molecule, cleaved HK, is designated cleaved High-Molecular-Weight Kininogen or HKa. While BK has been intensively studied, the physiological implication of the generation of HKa is not clear. Recent studies have revealed that HKa inhibits angiogenesis while BK promotes angiogenesis. These findings represent novel functions of the kallikrein–kinin system that have not yet been fully appreciated. In this review, we will briefly discuss the recent progress in the studies of the molecular mechanisms that mediate the antiangiogenic effect of HKa and the proangiogenic activity of BK.
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inhibition of tumor angiogenesis in vivo by a monoclonal antibody targeted to domain 5 of high molecular weight Kininogen
Blood, 2004Co-Authors: James S Song, Harlan N. Bradford, Robin A Pixley, Irma Isordiasalas, Irma M Sainz, Stephen C Cosenza, Abdel Bior, Yanlin Guo, Premkumar E Reddy, Robert W. ColmanAbstract:We have shown that human high molecular weight Kininogen is proangiogenic due to release of bradykinin. We now determined the ability of a murine monoclonal antibody to the light chain of high molecular weight Kininogen, C11C1, to inhibit tumor growth compared to isotype-matched murine IgG. Monoclonal antibody C11C1 efficiently blocks binding of high molecular weight Kininogen to endothelial cells in a concentration-dependent manner. The antibody significantly inhibited growth of human colon carcinoma cells in a nude mouse xenograft assay and was accompanied by a significant reduction in the mean microvascular density compared to the IgG control group. We also showed that a hybridoma producing monoclonal antibody C11C1 injected intramuscularly exhibited markedly smaller tumor mass in a syngeneic host compared to a hybridoma producing a monoclonal antibody to the high molecular weight Kininogen heavy chain or to an unrelated plasma protein. In addition, tumor inhibition by purified monoclonal antibody C11C1 was not due to direct antitumor effect because there was no decrease of tumor cell growth in vitro in contrast to the in vivo inhibition. Our results indicate that monoclonal antibody C11C1 inhibits angiogenesis and human tumor cell growth in vivo and has therapeutic potential for treatment of human cancer. (Blood. 2004;104:2065-2072)
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Upregulation of Cdc2 and cyclin A during apoptosis of endothelial cells induced by cleaved High-Molecular-Weight Kininogen.
American journal of physiology. Heart and circulatory physiology, 2003Co-Authors: Shujie Wang, Robert W. Colman, Irma Isordia-salas, Muneer G. Hasham, Alexander Y. Tsygankov, Yanlin GuoAbstract:We (8) reported that the cleaved High-Molecular-Weight Kininogen (HKa) and its domain 5 (D5) inhibited angiogenesis. Further studies (15) revealed that D5 could inhibit cell proliferation and induc...