doi: 10.1161/01.CIR.0000153852.22772.A6
(Circulation. 2005;111:e38-e39.)
© 2005 American Heart Association, Inc.
Correspondence |
Letter Regarding Article by Augé et al, "Role for Matrix Metalloproteinase-2 in Oxidized Low- Density Lipoprotein-Induced Activation of the Sphingomyelin/Ceramide Pathway and Smooth Muscle Cell Proliferation"
Cardiology Clinic, Kosuyolu Heart and Research Hospital, 
stanbul, Turkey, cemil_izgi{at}yahoo.com
We have read the recent article by Augé et al1 with great interest. The authors demonstrated the role of matrix metalloproteinase (MMP)-2 in oxidized (ox)-LDL–induced sphingolipid signaling and smooth muscle cell (SMC) proliferation. We have several comments about their findings and statements.
The authors depicted the activated neutral sphingomyelinase (SMase) as the membrane-bound form of the enzyme. However, as far as we know, the precise cellular localization of the signaling sphingomyelinase in the ox-LDL–treated SMC is still not exactly clear.
Wherever the enzyme is located, the critical point, as stated also by the authors, is how the extracellular ox-LDL is linked to the signaling SMase. The authors suggest this link to be MMP-2, subsequent to its activation by membrane type 1 (MT1)-MMP. However, although the results of their experiments underline the novel, crucial role of both MT1-MMP and MMP-2 in ox-LDL–induced SMase activation, they do not discriminate whether MT1-MMP or MMP-2 is the final link to SMase activation and SMC proliferation.
MT1-MMP, with its already existing link to the cytoplasm by its intracytoplasmic domain and predominant location in the caveolae, takes part in signal transduction and ERK activation2 and may also be the link between ox-LDL and SMase. The experiments by Gingras et al2 showed that MT1-MMP induced ERK activation when overexpressed in migrating endothelial cells. However, this effect was abolished when a catalytically inactive mutated form of MT1-MMP, which was unable to activate proMMP-2, was expressed or when a tissue inhibitor of MMP-2 activation, TIMP-2, was added. When the intracytoplasmic domain partially truncated mutant of MT1-MMP was expressed, ERK activation did not occur although MMP-2 activation was still occurring. Thus, MT1-MMP–induced MMP-2 activation is a prerequisite, however it is not sufficient to activate ERK, which is dependent on MT1-MMP–induced signaling by its cytoplasmic domain. Although this cascade may be cell type specific and may not necessarily operate in SMC, catalytically active and substrate (MMP-2) available MT1-MMP rather than MT1-MMP–activated MMP-2 may be the link for ox-LDL–induced SMase activation and SMC proliferation.
Finally, besides the relatively predictable effect that statins—by reducing MMP-2 expression—may have on this signaling cascade, whether it will also be affected by cyclooxygenase inhibitors, which dose dependently increase the SMase activator arachidonate levels,3 will be of great concern.
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 Top References References |
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1. Augé N, Maupas-Schwalm F, Elbaz M, Thiers JC, Waysbort A, Itohara S, Krell HW, Salvayre R, Nègre-Salvayre A. Role for matrix metalloproteinase-2 in oxidized low-density lipoprotein-induced activation of the sphingomyelin/ceramide pathway and smooth muscle cell proliferation. Circulation. 2004; 110: 571–578.
2. Gingras D, Bousquet-Gagnon N, Langlois S, Lachambre MP, Annabi B, Beliveau R. Activation of the extracellular signal-regulated protein kinase cascade by membrane-type-1 matrix metalloproteinase (MT1-MMP). FEBS Lett. 2001; 507: 231–236.[CrossRef][Medline] [Order article via Infotrieve]
3. Hannun YA, Luberto C, Argraves KM. Enzymes of sphingolipid metabolism: from modular to integrative signaling. Biochemistry. 2001; 40: 4893–4903.[CrossRef][Medline] [Order article via Infotrieve]
Response
INSERM U-466, Department of Biochemistry, CHU Rangueil, Toulouse, France
INSERM U-466, Departments of Biochemistry and Cardiology, CHU Rangueil, Toulouse, France
Roche Diagnostics GmbH, Penzberg, Germany
RIKEN Brain Science Institute, Wako-Shi, Saitama, Japan
We thank Dr Izgi and colleagues for their interest in our article.1
The subcellular localization of the neutral sphingomyelinase involved in cell signaling remains unclear. The neutral sphingomyelinases are generally considered as membrane-associated enzymes,2 and, recently, the neutral sphingomyelinase-2 involved in cell signaling has been shown to translocate at the plasma membrane.3 Moreover, as a large part of the substrate (sphingomyelin) is located in rafts/caveolae, and as membrane type 1 matrix metalloproteinase (MT1-MMP) and MMP-2 have also been localized in rafts, it is not excluded that the interaction between these metalloproteases and the neutral sphingomyelinase may occur in rafts/caveolae. However, this attractive hypothesis remains to be firmly demonstrated.
Our data show, for the first time, that both MT1-MMP and MMP-2 are required for the oxidized LDL (oxLDL)–induced activation of the neutral sphingomyelinase and subsequent sphingomyelin/ceramide pathway, as assessed by the use of pharmacological inhibitors, anti-MMP-2 and anti–MT1-MMP blocking antibodies, small-interference RNA directed to MMP-2, fibroblasts from MMP-2–/– mice, and recombinant (r) MT1-MMP and rMMP-2. But our data do not exclude the hypothesis of Gingras et al4 that endogenous MT1-MMP could act as coactivator by its cytoplasmic domain. The molecular mechanisms by which MT1-MMP and MMP-2 activate the neutral sphingomyelinase remain unanswered because, to date, several questions concerning the nature and precise localization of this sphingomyelinase are unknown. For instance, we do not know whether (1) MT1-MMP and MMP-2 act directly on the neutral sphingomyelinase or on regulatory proteins (activator or inhibitor or adaptor?); (2) MT1-MMP and MMP-2 act only by their proteolytic activity or require the coactivating cytoplasmic domain of MT1-MMP, according to Gringas et al4; (3) MMP-2 activation requires the formation of a complex involving TIMP-2, activator(s), MT1-MMPs, and integrins as a docking system5; or (4) sphingomyelinase activation is regulated by proteins of the extracellular matrix (collagen IV, elastin, and thrombospondin) that are known to regulate MT1-MMP and MMP-2.5
Finally, our report is focused on the novel role of MT1-MMP and MMP-2 as activators of the signaling sphingomyelinase activated by oxLDL, but the fine molecular mechanisms linking these metalloproteases to the (yet-unidentified) neutral sphingomyelinase remain to be elucidated.
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TopReferencesReferences |
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1. Augé N, Maupas-Schwalm F, Elbaz M, Thiers JC, Waysbort A, Itohara S, Krell HW, Salvayre R, Nègre-Salvayre A. Role for matrix metalloproteinase-2 in oxidized low-density lipoprotein-induced activation of the sphingomyelin/ceramide pathway and smooth muscle cell proliferation. Circulation. 2004; 110: 571–578.
2. Kronke M. Involvement of sphingomyelinases in TNF signaling pathways. Chem Phys Lipids. 1999; 102: 157–166.[CrossRef][Medline] [Order article via Infotrieve]
3. Marchesini N, Osta W, Bielawski J, Luberto C, Obeid LM, Hannun YA. Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells. J Biol Chem. 2004; 279: 25101–111.
4. Gingras D, Bousquet-Gagnon N, Langlois S, Lachambre MP, Annabi B, Beliveau R. Activation of the extracellular signal-regulated protein kinase cascade by membrane-type-1 matrix metalloproteinase (MT1-MMP). FEBS Lett. 2001; 507: 231–236.[CrossRef][Medline] [Order article via Infotrieve]
5. Hornebeck W, Emonard H, Monboisse JC, Bellon G. Matrix-directed regulation of pericellular proteolysis and tumor progression. Semin Cancer Biol. 2002; 12: 231–241.[CrossRef][Medline] [Order article via Infotrieve]
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