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Cardiovascular Research 2004 63(4):625-634; doi:10.1016/j.cardiores.2004.05.008
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Cyclic strain-mediated regulation of endothelial matrix metalloproteinase-2 expression and activity

Nicholas von Offenberg Sweeneya, Philip M Cummins*,a, Yvonne A Birneya, John P Cullenb, Eileen M Redmondb and Paul A Cahilla

aVascular Health Research Centre, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin 9, Ireland
bDepartment of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA

* Corresponding author. Tel.: +353-1-700-8499; fax: +353-1-700-5412. Email address: phil.cummins{at}dcu.ie

Objective: To investigate the role of cyclic strain in controlling matrix metalloproteinase-2 (MMP-2) expression and activity in endothelial cells (ECs) in vitro. Methods: A Flexercell® Tension PlusTM FX-4000TTM system was used to apply a physiological level of equibiaxial cyclic strain (0–10% strain, 60 cycles/min, 0–24 h, cardiac waveform) to bovine aortic endothelial cells (BAECs). Cells and conditioned media were harvested for analysis of MMP-2/9 expression and activity (pro and active) using reverse-transcriptase polymerase chain reaction (RT-PCR), Western blotting and zymography techniques. Results: Cyclic strain significantly increased MMP-2 expression and activity force- and time-dependently. Pretreatment with Gi{alpha}-protein inhibitors, pertussis toxin (PTX) and NF023, transient expression of inhibitory mutants of Gi{alpha}-subunits, or pretreatment with RGD peptides to block RGD-dependent integrin signaling failed to attenuate strain-induced increases in MMP-2 expression in BAECs. In contrast, inhibition of Gβ{gamma}-signaling with βArk-ct or tyrosine kinase blockade with genistein reduced strain-induced MMP-2 expression while concomitantly inhibiting strain-induced p38 and ERK activity in these cells. Pretreatment with PD169316 and PD98059 to selectively inhibit p38 and ERK activity, respectively, also resulted in a significant inhibition of the strain-induced MMP-2 response. Finally, inhibition of the adaptor protein, Shc, (via Shc-SH2 transfection) resulted in a significant decrease in strain-induced MMP-2 activity concomitant with a reduction in ERK activity in BAECs. Conclusion: Cyclic strain stimulates MMP-2 expression, in part, by stimulating both p38- and ERK-dependent pathways through activation of Gβ{gamma} and tyrosine kinase in BAECs.

KEYWORDS MMP-2; Endothelial matrix metalloproteinase; Cyclic strain-mediated regulation

Time for primary review 32 days


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