Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2

Abstract

Mignatti. Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2. Am J Physiol Heart Circ Physiol 290: H1651-H1659, 2006. First published November 11, 2005 doi:10.1152/ajpheart.00530.2005.-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-␣ (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 arterializationinduced 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.inflammation; mitogen-activated protein kinase; vascular remodeling VEIN GRAFT exposure to arterial circulation often results in intimal hyperplasia and medial hypertrophy, with eventual luminal stenosis and reocclusion. The process of vein graft stenosis involves migration and proliferation of smooth muscle cells (SMCs), along with excess deposition of extracellular proteins such as collagen (44).Matrix metalloproteinases (MMPs), a family of zinc-and calcium-dependent proteinases, collectively degrade all protein components of the extracellular matrix (ECM; 21). SMCs and macrophages in atherosclerotic and balloon-injured arteries express increased levels of MMP-9, MMP-2, and membranetype 1 metalloproteinase (MT1-MMP) (30). MMP-2 appears to have particular requirements for activation, entailing interaction with plasma membrane-tethered MMPs (the MT-MMPs) and formation of a trimolecular complex consisting of proMMP-2, MT-MMP, and tissue inhibitor of metalloproteinases-2 (TIMP-2) (38). MT1-MMP-bound MMP-2 is also activated by thrombin (23), plasmin, and neutrophil prote...

Mechanisms of Vascular Smooth Muscle Cell Migration

“…126 Indirect, longer-term effects on cell migration might be exerted by regulating transcription factors that control expression of promigratory growth factors, matrix proteins, and matrix metalloproteinases. 127,128 The p38 MAPK cascade has also been implicated in VSM cell migration with the use of both chemical inhibitors of p38 MAPK and gene transfer approaches. A signaling cascade comprising MAPK kinase 3 (MKK3), p38 MAPKs, MAPK activated protein kinase 2 (MK2), and heat shock protein 27 (HSP27) is necessary for migration of both smooth muscle cells 129,130 and endothelial cells.…”

Antimetastatic effect of nobiletin through the down-regulation of CXC chemokine receptor type 4 and matrix metallopeptidase-9

“…Huang et al demonstrates that stromal cell-derived factor-1/CXCR4 enhances the motility of human osteosarcoma cells that involve MEK1/2, ERK and NF-κB-dependent pathways (Huang et al, 2009); in addition, CXCR4 mediates the homing of B cell progenitor acute lymphoblastic leukaemia cells to the bone marrow via the activation of p38MAPK (Juarez et al, 2009). Moreover, the reduction of ERK1/2 signaling pathways resulted in the inhibition of MMP-9 expression in arterialized vein grafts (Sharony et al, 2006), a p38 MAPK inhibitor (SB203580) suppresses the regulation of MMP-9 in cancer cells (Simon et al, 1998), and the suppression of the JNK pathway leads to a downregulated PMA-induced MMP-9 expression (Lee et al, 2008). Thus, in our study, the inhibitory effects of nobiletin on the expressions of CXCR4 and MMP-9 may be mediated in part through the inactivation of the MAPKs pathways.…”

Thrombin cleaves the high molecular weight forms of basic fibroblast growth factor (FGF-2): a novel mechanism for the control of FGF-2 and thrombin activity

“…While investigating vascular responses to vein graft arterialization, we found a dramatic and rapid increase in vein graft-associated thrombin activity (Sharony et al, 2006). Because this effect was paralleled by an apparent increase in LMW FGF-2 and disappearance of HMW FGF-2 in the vein grafts, we hypothesized that thrombin cleaves HMW FGF-2 into LMW forms in vascular cells.…”