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

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.

[1]  Z. Ruggeri,et al.  Signaling Through GP Ib-IX-V Activates αIIbβ3 Independently of Other Receptors , 2004 .

[2]  A. Strongin,et al.  Membrane type‐1 matrix metalloproteinase stimulates tumour cell‐induced platelet aggregation: role of receptor glycoproteins , 2004, British journal of pharmacology.

[3]  J. Hartwig,et al.  Metalloproteinase inhibitors improve the recovery and hemostatic function of in vitro-aged or -injured mouse platelets. , 2003, Blood.

[4]  S. Apte,et al.  Matrix metalloproteinases: old dogs with new tricks , 2003, Genome Biology.

[5]  M. Radomski,et al.  Inhaled nitric oxide inhibits the release of matrix metalloproteinase-2, but not platelet activation, during extracorporeal membrane oxygenation in adult rabbits. , 2003, Journal of pediatric surgery.

[6]  D. Essex,et al.  Redox control of platelet aggregation. , 2003, Biochemistry.

[7]  C. Overall,et al.  Identification, regulation and role of tissue inhibitor of metalloproteinases‐4 (TIMP‐4) in human platelets , 2002, British journal of pharmacology.

[8]  A. Weyrich,et al.  Outside-In Signals Delivered by Matrix Metalloproteinase-1 Regulate Platelet Function , 2002, Circulation research.

[9]  P. Jurasz,et al.  Nonremodeling properties of matrix metalloproteinases: the platelet connection. , 2002, Circulation research.

[10]  J. Baselga,et al.  Metalloprotease-dependent Protransforming Growth Factor-α Ectodomain Shedding in the Absence of Tumor Necrosis Factor-α-converting Enzyme* , 2001, The Journal of Biological Chemistry.

[11]  P. Jurasz,et al.  Pharmacological characteristics of solid‐phase von Willebrand factor in human platelets , 2001, British journal of pharmacology.

[12]  J W Smith,et al.  Mechanism of integrin activation by disulfide bond reduction. , 2001, Biochemistry.

[13]  M. Radomski,et al.  Matrix metalloproteinase-2 in platelet adhesion to fibrinogen: interactions with nitric oxide. , 2001, Medical science monitor : international medical journal of experimental and clinical research.

[14]  I. Elalamy,et al.  Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation. , 2000, Blood.

[15]  M. Radomski,et al.  Differential Regulation of Platelet Aggregation by Matrix Metalloproteinases-9 and -2 , 1999, Thrombosis and Haemostasis.

[16]  J. Elferink.  Thimerosal: a versatile sulfhydryl reagent, calcium mobilizer, and cell function-modulating agent. , 1999, General pharmacology.

[17]  S Zucker,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* , 1998, The Journal of Biological Chemistry.

[18]  M. Radomski,et al.  Localization and Translocation of MMP-2 during Aggregation of Human Platelets , 1998, Thrombosis and Haemostasis.

[19]  R. Fridman,et al.  Phorbol ester-induced cell surface association of matrix metalloproteinase-9 in human MCF10A breast epithelial cells. , 1997, Cancer research.

[20]  M. V. van Dam-Mieras,et al.  Effect of membrane-permeable sulfhydryl reagents and depletion of glutathione on calcium mobilisation in human platelets. , 1997, Biochemical pharmacology.

[21]  M. Radomski,et al.  Release of gelatinase A during platelet activation mediates aggregation , 1997, Nature.

[22]  Yi Sun,et al.  Activation of p53 transcriptional activity by 1,10-phenanthroline, a metal chelator and redox sensitive compound , 1997, Oncogene.

[23]  A. Rehemtulla,et al.  Membrane Type Matrix Metalloproteinase 1 Activates Pro-gelatinase A without Furin Cleavage of the N-terminal Domain* , 1996, The Journal of Biological Chemistry.

[24]  M. Scully,et al.  Increased expression of procoagulant activity on the surface of human platelets exposed to heavy-metal compounds. , 1995, The Biochemical journal.

[25]  G Murphy,et al.  A novel coumarin‐labelled peptide for sensitive continuous assays of the matrix metalloproteinases , 1992, FEBS letters.

[26]  B. Wachowicz,et al.  Effects of mercurial compounds on adenine nucleotides of washed pig platelets. , 1983, Environmental research.

[27]  G. Ball,et al.  Effect of some inhibitors of platelet aggregation on platelet nucleotides. , 1969, The Biochemical journal.

[28]  P. Jurasz,et al.  Matrix metalloproteinase-2 contributes to increased platelet reactivity in patients with metastatic prostate cancer: a preliminary study. , 2003, Thrombosis research.

[29]  P. Jurasz,et al.  Matrix metalloproteinase 2 in tumor cell-induced platelet aggregation: regulation by nitric oxide. , 2001, Cancer research.

[30]  J. Baselga,et al.  Metalloprotease-dependent protransforming growth factor-alpha ectodomain shedding in the absence of tumor necrosis factor-alpha-converting enzyme. , 2001, The Journal of biological chemistry.

[31]  P. Thompson,et al.  The effects of varying doses of aspirin on human platelet activation induced by PAF, collagen and arachidonic acid. , 1992, British journal of clinical pharmacology.

[32]  H. Birkedal‐Hansen,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. , 1990, Proceedings of the National Academy of Sciences of the United States of America.