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

doi:10.1016/j.cardiores.2004.05.008

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

Nicholas von Offenberg Sweeney^a, Philip M Cummins^*^,a, Yvonne A Birney^a, John P Cullen^b, Eileen M Redmond^b and Paul A Cahill^a

^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 controllingmatrix metalloproteinase-2 (MMP-2) expression and activity inendothelial cells (ECs) in vitro. Methods: A Flexercell®Tension Plus^TM FX-4000T^TM system was used to apply a physiologicallevel of equibiaxial cyclic strain (0–10% strain, 60 cycles/min,0–24 h, cardiac waveform) to bovine aortic endothelialcells (BAECs). Cells and conditioned media were harvested foranalysis of MMP-2/9 expression and activity (pro and active)using reverse-transcriptase polymerase chain reaction (RT-PCR),Western blotting and zymography techniques. Results: Cyclicstrain significantly increased MMP-2 expression and activityforce- and time-dependently. Pretreatment with Gi ${alpha}$ -protein inhibitors,pertussis toxin (PTX) and NF023, transient expression of inhibitorymutants of Gi ${alpha}$ -subunits, or pretreatment with RGD peptides toblock RGD-dependent integrin signaling failed to attenuate strain-inducedincreases in MMP-2 expression in BAECs. In contrast, inhibitionof Gβ ${gamma}$ -signaling with βArk-ct or tyrosine kinase blockadewith genistein reduced strain-induced MMP-2 expression whileconcomitantly inhibiting strain-induced p38 and ERK activityin these cells. Pretreatment with PD169316 and PD98059 to selectivelyinhibit p38 and ERK activity, respectively, also resulted ina significant inhibition of the strain-induced MMP-2 response.Finally, inhibition of the adaptor protein, Shc, (via Shc-SH2transfection) resulted in a significant decrease in strain-inducedMMP-2 activity concomitant with a reduction in ERK activityin BAECs. Conclusion: Cyclic strain stimulates MMP-2 expression,in part, by stimulating both p38- and ERK-dependent pathwaysthrough 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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