Plasma urokinase antigen levels predict angiographic restenosis

Strauss, B.H.; Singh, I.; Lau, Hung; Bowman, Kimberley A.; Teitel, Jerome; Sparkes, John D.; Garvery, M.B.; Natarajan, Madhu K.; Chisholm, Robert J.

doi:10.1016/s0735-1097(98)81265-5

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“…The migration of vascular smooth muscle cells (VSMC) involves the complex regulation of proteases, integrins and extracellular molecules leading to the sequence of attachment, detachment and contraction events, which allow a cell to move through the extracellular matrix. Urokinase plasminogen activator (uPA) is a serine protease that is the primary plasminogen activator in tissue remodeling processes and increased serum uPA is associated with development of restenosis after coronary angioplasty (2). In addition to its extracellular proteolytic activity, uPA is also capable of mediating cell signaling.…”

Section: Introductionmentioning

confidence: 99%

Cell migration in response to the amino-terminal fragment of urokinase requires epidermal growth factor receptor activation through an ADAM-mediated mechanism

Bakken

Protack

Roztocil

et al. 2009

Journal of Vascular Surgery

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Background Cell migration is an integral component of intimal hyperplasia development and proteases are pivotal in the process. Understanding the role of urokinase signaling within the cells of vasculature remains poorly defined. The study examines the role of aminoterminal fragment of urokinase (ATF) on a pivotal cross-talk receptor, Epidermal Growth Factor Receptor (EGFR). EGFR is transactivated by both G-protein-coupled receptors and receptor tyrosine kinases and is key to many of their responses. We hypothesize that ADAM allows the transactivation of EGFR by ATF. Objective To determine the role of ADAM in EGFR transactivation by ATF in human vascular smooth muscle cells (VSMC) ) during cell migration. Methods Human coronary VSMC were cultured in vitro. Assays of EGFR phosphorylation were examined in response to ATF (10nM) in the presence and absence of the matrix metalloprotease (MMP) inhibitor GM6001, the ADAM inhibitors TAPI-0 and TAPI-1, Heparin binding epidermal growth factor (HB-EGF) inhibitor, CRM197, HB-EGF inhibitory antibodies, EGF inhibitory antibodies and the EGFR inhibitor AG1478. siRNA against EGFR and ADAM (9,10,12) and adenoviral delivered Gβγ inhibitor, βARKCT were also used. Results ATF produced concentration dependent VSMC migration (by wound assay and boyden chamber), which was inhibited by increasing concentrations of AG1478. ATF was shown to induce time-dependent EGFR phosphorylation, which peaked at 4-fold greater than control. Pre-incubation with the Gβγ inhibitor, βARKCT inhibited EGFR activation by ATF. This migratory and EGFR response was inhibited by AG1478 in a concentration-dependent manner. Incubation with siRNA against EGFR blocked the ATF mediated migratory and EGFR responses.. EGFR phosphorylation by ATF was blocked by inhibition of MMP activity and the ligand HB-EGF. The presence of the ADAM inhibitors, TAPI-0 and TAPI-1 significantly decreased EGFR activation. EGFR phosphorylation by EGF was not interrupted by inhibition of MMP, ADAMs, or HB-EGF. Direct blockade of the EGFR prevented activation by both ATF and EGF. Incubation with siRNA to ADAM-9 and -10 significantly reduced HB-EGF release from VSMC and EGFR activation in response to ATF. siRNA against ADAM-12 had no effect. Conclusion ATF can induce transactivation of EGFR by an ADAM-mediated, HB-EGF dependent process. Targeting a pivotal cross-talk receptor such as EGFR is an attractive molecular target to inhibit cell migration

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Section: Introductionmentioning

confidence: 99%