Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2.
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 membrane-type 1-MMP (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 mitogen-activated protein kinase kinase (MEK-1/2) inhibitor UO126 for 30 min before being grafted. Vein graft extracts were analyzed for MMPs, TIMP-2, tumor necrosis factor-alpha (TNF-alpha), 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-alpha 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-alpha 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.
Sharony
Ram
R
Depts. of Cardiothoracic Surgery, New York Univesity School of Medicine, New York, NY 10016, USA.
Pintucci
Giuseppe
G
Saunders
Paul C
PC
Grossi
Eugene A
EA
Baumann
F Gregory
FG
Galloway
Aubrey C
AC
Mignatti
Paolo
P
D000714:Anastomosis, Surgical; D000818:Animals; D002339:Carotid Arteries / Q000276:immunology / Q000601:surgery; D004285:Dogs; D018836:Inflammation Mediators / Q000276:immunology*; D007601:Jugular Veins / Q000276:immunology* / Q000637:transplantation*; D020782:Matrix Metalloproteinases / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
D018836:Inflammation Mediators; D019716:Tissue Inhibitor of Metalloproteinase-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020782:Matrix Metalloproteinases