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Thromb Haemost 2005; 93(02): 326-330
DOI: 10.1160/TH04-08-0541
Platelets and Blood Cells
Schattauer GmbH

The organomercurial 4-aminophenylmercuric acetate, independent of matrix metalloproteinases, induces dose-dependent activation/ inhibition of platelet aggregation

Mathias T. Rosenfeldt   *
1   Department of Medicine, Veterans Affairs Medical Center, Northport, New York, USA
,
Michael Valentino
1   Department of Medicine, Veterans Affairs Medical Center, Northport, New York, USA
,
Salvatore Labruzzo
1   Department of Medicine, Veterans Affairs Medical Center, Northport, New York, USA
,
Lesley Scudder
2   Department of Medicine, State University of New York at Stony Brook, New York, USA
,
Maria Pavlaki
2   Department of Medicine, State University of New York at Stony Brook, New York, USA
,
Jian Cao
2   Department of Medicine, State University of New York at Stony Brook, New York, USA
,
Jeffrey Vacirca
1   Department of Medicine, Veterans Affairs Medical Center, Northport, New York, USA
2   Department of Medicine, State University of New York at Stony Brook, New York, USA
,
Wadie F. Bahou   †
2   Department of Medicine, State University of New York at Stony Brook, New York, USA
,
Stanley Zucker   †
1   Department of Medicine, Veterans Affairs Medical Center, Northport, New York, USA
2   Department of Medicine, State University of New York at Stony Brook, New York, USA
› Author AffiliationsFinancial support: This research was supported by Merit Review and REAP grants from the Department of Veterans Affairs (S.Z.), NIH Center grant MO1 10710–5 to the University Hospital General Clinical Research Center, grants from the National Institutes of Health (NHL49141 and NHL53665 [W.B.]), an American Heart Association Fellowship (J.C.) and a grant from the US Army Materiel Command (J.C.)
Further Information

Publication History

Received 24 August 2004

Accepted after revision 25 January 2004

Publication Date:
11 December 2017 (online)

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Summary

Matrix metalloproteinases (MMPs) play an important role in many biological and pathological processes including tissue remodeling, wound healing, inflammation, atherosclerosis, and cancer. Numerous publications have supported the concept that activated MMP-2 enhances agonist-induced platelet aggregation and activated MMP-9 inhibits platelet aggregation. In this study, we demonstrated that the organomercurial compound, 4-aminophenyl mercuric acetate (APMA), which is routinely employed to activate latent MMPs at a concentration of 1000 μ M, induces platelet aggregation at low concentration (5 μ M) and inhibits agonist-induced platelet aggregation at concentrations ≥ 50 μ M. Activated MMP-2, MMP-1, and MMP-9, following removal of APMA by ultrafiltration through an anisotropic membrane, exert no independent effect on platelet aggregation. Acetylsalicylic acid and BAPTA inhibited APMA-induced platelet aggregation indicating that the APMA mediated pathway of platelet activation is dependent upon thromboxane and calcium signaling. Zinc chelation with 1,10-phenanthroline, which inhibits zincdependent proteins including metalloproteinases, also abrogated platelet functional responses to APMA. Additional studies will be required to clarify the mechanism of the biphasic effect of APMA on platelet aggregation.

Keywords

Matrix metalloproteinases (MMP) - platelet aggregation - 4-aminophenylmercuric acetate (APMA)

* Present address: Department of Hematology, Oncology and Tumor Immunology, Humboldt-University/Charité, Berlin, Germany. This work was done while Mathias Rosenfeldt was a visiting medical student at Northport VA Medical Centre


† Both senior authors contributed equally to this project


 

  • References

  • 1 Somerville RPT. et al Matrix metalloproteinases: old dogs with new tricks.. Genome Biol 2003; 4: 216
    CrossrefPubMedGoogle Scholar
  • 2 Sawicki G. et al Release of gelatinase A during platelet activation mediates aggregation.. Nature 1997; 386: 616-9.
    CrossrefPubMedGoogle Scholar
  • 3 Fernandez-Patron C. et al Differential regulation of platelet aggregation by matrix metalloproteinases-9 and –2.. Thromb Haemost 1999; 82: 1730-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Galt SW. et al Outside-in signals delivered by matrix metalloproteinase-1 regulate platelet function.. Circ Res 2002; 90: 1093-9.
    CrossrefPubMedGoogle Scholar
  • 5 Radomski A. et al Identification, regulation and role of tissue inhibitor of metalloproteinases-4 (TIMP-4) in human platelets.. Br J Pharmacol 2002; 137: 1330-8.
    CrossrefPubMedGoogle Scholar
  • 6 Kazes I, Elalamy I, Sraer JD. et al Platelet release of trimolecular complex components MT1-MMP/ TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation.. Blood 2000; 96: 3064-9.
    CrossrefPubMedGoogle Scholar
  • 7 Sawicki G, Sanders EJ, Salas E. et al Localization and translocation of MMP-2 during aggregation of human platelets.. Thromb Haemost 1998; 80: 836-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Jurasz P. et al Matrix metalloproteinase-2 contributes to increased platelet reactivity in patients with metastatic prostate cancer: a preliminary study.. Thromb Res 2003; 112: 59-64.
    CrossrefPubMedGoogle Scholar
  • 9 Cheung PY. et al Inhaled nitric oxide inhibits the release of matrix metalloproteinase-2, but not platelet activation, during extracorporeal membrane oxygenation in adult rabbits.. J Pediatr Surg 2003; 38: 534-8.
    CrossrefPubMedGoogle Scholar
  • 10 Jurasz P, Chung AW, Radomski A. et al Nonremodeling properties of matrix metalloproteinases: the platelet connection.. Circ Res 2002; 90: 1041-3.
    CrossrefPubMedGoogle Scholar
  • 11 Radomski A. et al Pharmacological characteristics of solid-phase von Willebrand factor in human platelets.. Br J Pharmacol 2001; 134: 1013-20.
    CrossrefPubMedGoogle Scholar
  • 12 Martinez A. et al Matrix metalloproteinase-2 in platelet adhesion to fibrinogen: interactions with nitric oxide.. Med Sci Monit 2001; 7: 646-51.
    PubMedGoogle Scholar
  • 13 Jurasz P. et al Matrix metalloproteinase 2 in tumor cell-induced platelet aggregation: regulation by nitric oxide.. Cancer Res 2001; 61: 376-82.
    PubMedGoogle Scholar
  • 14 Alonso-Escolano D. et al Membrane type-1 matrix metalloproteinase stimulates tumour cell-induced platelet aggregation: role of receptor glycoproteins.. Br J Pharmacol 2004; 141: 241-52.
    CrossrefPubMedGoogle Scholar
  • 15 Springman EB. et al Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a "cysteine switch" mechanism for activation.. Proc Natl Acad Sci 1990; 87: 364-8.
    CrossrefPubMedGoogle Scholar
  • 16 Cao J. et al The propeptide domain of membrane type 1 matrix metalloproteinase is required for binding of tissue inhibitor of metalloproteinases and for activation of pro-gelatinase A.. J Biol Chem 1998; 273: 34745-52.
    CrossrefPubMedGoogle Scholar
  • 17 Toth M. et al Phorbol ester-induced cell surface association of matrix metalloproteinase-9 in human MCF10A breast cancer cells.. Cancer Res 1997; 57: 3159-67.
    PubMedGoogle Scholar
  • 18 Cao J. et al Membrane type matrix metalloproteinase 1 activates pro-gelatinase A without furin cleavage of the N-terminal domain.. J Biol Chem 1996; 271: 30174-80.
    CrossrefPubMedGoogle Scholar
  • 19 Knight CG. et al A novel coumarin-labelled peptide for sensitive continuous assays of the matrix metalloproteinases.. FEBS Lett 1992; 296: 263-6.
    CrossrefPubMedGoogle Scholar
  • 20 Taylor ML. et al The effects of varying doses of ASA on human platelet activation induced by PAF, collagen and arachidonic acid.. Br J Clin Pharmacol 1992; 33: 25-31.
    CrossrefPubMedGoogle Scholar
  • 21 Kasirer-Friede A. et al Signalling through GP Ib- IX-V activates α IIbβ 3 independently of other receptors.. Blood 2004; 103: 3403-11.
    CrossrefPubMedGoogle Scholar
  • 22 Sun Y. et al Activation of p53 transcriptional activity by 1,10-phenanthroline, a metal chelator and redox sensitive compound.. Oncogene 1997; 14: 385-93.
    CrossrefPubMedGoogle Scholar
  • 23 Van Gorp RMA. et al Effect of membrane-permeable sulfhydryl reagents and depletion of glutathione on calcium mobilization in human platelets.. Biochem Pharmacol 1997; 53: 1533-42.
    CrossrefPubMedGoogle Scholar
  • 24 Ball G. et al Effect of some inhibitors of platelet aggregation on platelet nucleotides.. Biochem J 1969; 114: 669-71.
    CrossrefPubMedGoogle Scholar
  • 25 Elferink JGR. Thimerosal: a versatile sulfhydryl reagent, calcium mobilizer, and cell function-modulating agent.. Gen Pharmacol 1999; 33: 1-6.
    CrossrefPubMedGoogle Scholar
  • 26 Kostka B, Wachowiz B. Effect of mercurial compounds on adenine nucleotides of washed pig platelets.. Environmental Res 1983; 30: 420-6.
    CrossrefPubMedGoogle Scholar
  • 27 Goodwin CA. et al Increased expression of procoagulant activity on the surface of human platelets exposed to heavy-metal compounds.. Biochem J 1995; 308: 15-21.
    CrossrefPubMedGoogle Scholar
  • 28 Yan B, Smith JW. Mechanism of integrin activation by disulfide bond reduction.. Biochemistry 2001; 40: 8861-7.
    CrossrefPubMedGoogle Scholar
  • 29 Essex DW, Li M. Redox control of platelet aggregation.. Biochemistry 2003; 42: 129-36.
    CrossrefPubMedGoogle Scholar
  • 30 Bergmeier W. et al Metalloproteinase inhibitors improve the recovery and hemostatic function of in vitro-aged or -injured mouse platelets.. Blood 2003; 102: 4229-35.
    CrossrefPubMedGoogle Scholar
  • 31 Merlos-Suárez A. et al Metalloprotease-dependent protransforming growth factor-alpha ectodomain shedding in the absence of tumor necrosis factor-alpha-converting enzyme.. J Biol Chem 2001; 276: 48510-7.
    CrossrefPubMedGoogle Scholar