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1 Department of Cardiothoracic Surgery, Seymore Cohn Cardiovascular Surgery Research Laboratory, New York University, New York, NY, USA
2 Department of Cardiothoracic Surgery, Seymore Cohn Cardiovascular Surgery Research Laboratory, New York University, New York, NY, USA; Department of Cell Biology, New York Univesity, New York, NY, USA
* To whom correspondence should be addressed. E-mail: mignap01{at}med.nyu.edu.
Matrix metalloproteinases (MMPs) play key roles in vascular remodeling. We characterized the role of inflammatory mediators and extracellular signal-regulated kinases (ERKs) in the control of arterialized vein graft expression of MMP-9, MMP-2 and MT1-MMP and of the tissue inhibitor of metalloproteinases-2 (TIMP-2). For this purpose we used a canine model of jugular vein to carotid artery interposition graft and analyzed the vein grafts at various postoperative times (30 min to 28 days) using the contralateral vein as a control. To study the role of ERK-1/2 veins were incubated with the MAPK kinase (MEK-1/2) inhibitor UO126 for 30 min before grafting. Vein graft extracts were analyzed for MMPs, TIMP-2, tumor necrosis factor-alpha (TNF-
), polymorphonuclear neutrophil (PMN) infiltration, myeloperoxidase (MPO) and thrombin activity, and for ERK-1/2 activation. Vein graft arterialization resulted in rapid and sustained (8 h to 28 days) upregulation of vein graft-associated MMP-9, MMP-2, MT1-MMP, thrombin activity and TNF- levels, with concomitant TIMP-2 downregulation. MMP-2 activation preceded MT1-MMP upregulation. PMN infiltration and vein graft-associated MPO activity increased within hours after arterialization, indicating a prompt, local inflammatory response. In cultured smooth muscle cells, both thrombin and TNF- upregulated MT1-MMP expression; however, only thrombin activated MMP-2. Inhibition of ERK-1/2 activation blocked arterialization-induced upregulation of MMP-2, MMP-9 and MT1-MMP. Thus, thrombin, inflammatory mediators and activation of the ERK-1/2 pathway control MMP and TIMP-2 expression in arterialized vein grafts.
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