Thrombin‐induced platelet endostatin release is blocked by a proteinase activated receptor‐4 (PAR4) antagonist

Ma, Li; Hollenberg, Morley D.; Wallace, John L.

doi:10.1038/sj.bjp.0704312

Cited by 52 publications

(36 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…54 Activated platelets release endostatin. 55 In contrast to VEGF, platelet-derived endostatin seems to have only a minor influence on the total serum levels because: (i) serum endostatin levels are considerably higher than the serum levels of VEGF (measured in ng/ml vs. pg/ml); (ii) endostatin levels and platelet counts showed no correlation for untreated AML patients, and increased levels were observed even in thrombocytopenic AML patients; (iii) endostatin levels were not altered after the development of severe therapy-induced thrombocytopenia. We therefore regard our results to reflect true in vivo endostatin levels with only a minimal contribution from activated platelets during ex vivo serum preparation.…”

Section: Discussionmentioning

confidence: 99%

Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia

Glenjen

Mosevoll

Bruserud

2002

Intl Journal of Cancer

View full text Add to dashboard Cite

Angiogenesis seems to be important both in the pathogenesis of acute myelogenous leukemia (AML) and for the susceptibility of AML blasts to chemotherapy. Recent clinical studies even suggest that antiangiogenic therapy can induce disease control in patients with AML relapse. In this context we have investigated the profile of the systemic component of angiogenic regulation in AML by characterizing the serum levels of (i) the angiogenic regulators angiogenin, basic fibroblast growth factor (bFGF) and endostatin; (ii) the endothelial cell marker soluble (s) E-selectin. Patients with untreated AML had increased levels of angiogenin, endostatin and sEselectin, whereas the levels of bFGF were not significantly altered. The systemic levels of the proangiogenic bFGF, the antiangiogenic endostatin and the endothelial cell marker sE-selectin showed significant correlations, whereas angiogenin and sE-selectin levels were not correlated. Furthermore, intensive chemotherapy resulted in decreased systemic levels of the 2 proangiogenic mediators angiogenin and bFGF, whereas endostatin levels remained high after treatment. Although angiogenin normally is a part of the acute phase reaction, its systemic levels were not altered when patients with chemotherapy-induced cytopenia developed complicating bacterial infections. Our results suggest that intensive chemotherapy can modulate the systemic component of angiogenic regulation in AML patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia

Glenjen

Mosevoll

Bruserud

2002

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Efforts to develop receptor inhibitors as compared to targeting thrombin are currently regarded as a priority. As outlined in Table V ( [134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152], substantial success has been achieved in the development of PAR1 and PAR4 antagonists.…”

Section: Therapeutic Implications In Cancermentioning

confidence: 99%

Protease-activated receptors in cancer: A systematic review

Han

Jin

et al. 2011

Oncology Letters

View full text Add to dashboard Cite

Abstract. The traditional view of the role of proteases in tumor growth, progression and metastasis has significantly changed. Apart from their contribution to cancer progression, it is evident that a subclass of proteases, such as thrombin, serves as signal molecules controlling cell functions through the protease-activated receptors (PARs). Among the four types of PAR (PAR1-4; cloned and named in order of their discovery), PAR1, PAR3 and PAR4 are activated by thrombin, unlike PAR2, which is activated by trypsin-like serine proteases. Thrombin has been proven to be a significant factor in both the behavior of cancer in its involvement in hemostasis and blood coagulation. Thrombin is a key supporter of various cellular effects relevant to tumor growth and metastasis, as well as a potent activator of angiogenesis, which is essential for the growth and development of all solid tumor types. This review presents an overview of the role of PAR-mediated thrombin in angiogenesis and cancer, focusing on the ability of PAR1-and PAR4-mediated thrombin to affect tumorigenesis and angiogenesis.

show abstract

“…The PRP was maintained at 37°C and was continuously stirred at 900 rpm. Three minutes later, AY-NH 2 (2-32 M) was added to the platelet suspension in the absence or presence of transcinnamoyl (tcY)-YPGKF-NH 2 (tcY-NH 2 ; 400 M), a PAR4 antagonist (10,14), and aggregation was monitored for 5 min. The resulting platelet aggregate was centrifuged (9,000 ϫ g), and the supernatant was stored at Ϫ70°C until ELISA for endostatin were performed.…”

mentioning

confidence: 99%

Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets

Perini

McKnight

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

257

245

View full text Add to dashboard Cite

The roles of proteinase-activated receptors (PARs) in platelet functions other than aggregation are not well understood. Among these is the release of factors that regulate the process of angiogenesis, such as endostatin and VEGF, which, respectively, inhibit and promote angiogenesis. PAR1 and PAR4 are expressed on the surface of human platelets and can be activated by thrombin. In the present study, we have attempted to determine the roles of PAR1 and PAR4 in regulating release of endostatin and VEGF from human platelets. Aggregation and endostatin release could be elicited by a specific PAR4 agonist (AYPGKF-NH2). The PAR4 agonist concentration dependently suppressed VEGF release. A selective PAR1 agonist (TFLLR-NH2) induced platelet aggregation and VEGF release but suppressed endostatin release. Thrombin did not affect endostatin or VEGF release. However, in the presence of a selective PAR1 antagonist (SCH79797), thrombin stimulated endostatin release and suppressed VEGF release. Conversely, in the presence of a selective PAR4 antagonist (transcinnamoyl-YPGKF-NH2), thrombin stimulated VEGF release. In vivo, treatment of rats with established gastric ulcers with a PAR1 antagonist each day for 1 wk resulted in a significant retardation of healing. We conclude that PAR1 and PAR4 counter-regulate the release of endostatin and VEGF from platelets. These protease-activated receptors could therefore play a crucial role in regulating angiogenesis and in turn could regulate the processes of wound healing and tumor growth.angiogenesis ͉ aggregation ͉ thrombin ͉ protease I n addition to its central roles in blood coagulation and hemostasis, thrombin participates in a variety of biological processes, including inflammation and wound healing (1). Activation of platelets by thrombin is mediated at least in part through cleavage of proteinase-activated receptors (PARs). Four distinct PARs have been identified, with PAR1, PAR3, and PAR4 acting as receptors for thrombin. Human platelets express PAR1 and PAR4, and activation of either is sufficient to trigger platelet aggregation and secretion (2-5). A variety of bioactive substances, including growth factors and chemokines (6-8), are stored in platelets and released during activation. We have reported (9) that endostatin, a potent inhibitor of angiogenesis, is contained within rat platelets and released in response to thrombin via PAR4 in an aggregation-independent manner (10). In studies in rats, we demonstrated that pharmacological manipulation of platelet and͞or serum levels of proangiogenic (VEGF) and antiangiogenic (endostatin) factors resulted in profound effects on healing of gastric ulcers (11,12).Whether human platelets contain endostatin is unknown. Moreover, the relative importance of PAR1 vs. PAR4 in regulating platelet endostatin release has not been reported. In the present study, we have demonstrated that human platelets contain endostatin, and that its release can be triggered by activation of PAR4 but not PAR1. Indeed, PAR1 activation leads to suppression of e...

show abstract

Thrombin‐induced platelet endostatin release is blocked by a proteinase activated receptor‐4 (PAR4) antagonist

Cited by 52 publications

References 16 publications

Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia

Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia

Protease-activated receptors in cancer: A systematic review

Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets

Contact Info

Product

Resources

About