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(Circulation. 2004;110:571-578.)
© 2004 American Heart Association, Inc.

Original Articles

Role for Matrix Metalloproteinase-2 in Oxidized Low-Density Lipoprotein–Induced Activation of the Sphingomyelin/Ceramide Pathway and Smooth Muscle Cell Proliferation

Nathalie Augé, PhD; Françoise Maupas-Schwalm, MD; Meyer Elbaz, MD; Jean-Claude Thiers, MSc; Axel Waysbort, MD; Shigeyoshi Itohara, PhD; Hans-Willi Krell, PhD; Robert Salvayre, MD, PhD; Anne Nègre-Salvayre, PhD

From INSERM U-466, Department of Biochemistry (N.A., F.M.-S., M.E., J.-C.T., A.W., R.S., A.N.-S.) and Department of Cardiology (M.E.), CHU Rangueil, Toulouse, France; Roche Diagnostics GmbH, Penzberg, Germany (H.-W.K.); and RIKEN Brain Science Institute, Wako-Shi, Saitama, Japan (S.I.).

Correspondence to Dr A. Negre-Salvayre, Biochimie, INSERM U466, IFR-31, CHU Rangueil, 1, avenue Jean Poulhès, TSA-50032, 31059 Toulouse Cedex 9, France. E-mail anesalv{at}rangueil.inserm.fr or salvayre{at}rangueil.inserm.fr

Received July 8, 2003; de novo received December 26, 2003; revision received March 23, 2004; accepted March 30, 2004.

Background— Oxidized LDLs (oxLDLs) and matrix metalloproteinases (MMPs) are present in atherosclerotic lesions. OxLDLs activate various signaling pathways potentially involved in atherogenesis. OxLDLs induce smooth muscle cell (SMC) proliferation mediated by the activation of the sphingomyelin/ceramide pathway and tyrosine kinase receptors. MMPs are also able to induce SMC migration and proliferation in addition to extracellular matrix degradation. The present study was designed to investigate whether MMPs play a role in the mitogenic effect of oxLDLs.

Methods and Results— OxLDLs induce the release of activated MMP-2 in SMC culture medium. MMP-2 was identified by its 65-kDa gelatinase activity on zymography and by using specific blocking antibodies and MMP-2^–/– cells. MMP inhibitors (batimastat and Ro28-2653) and the blocking antibodies anti–MMP-2 and anti–membrane type 1-MMP inhibited the oxLDL-induced sphingomyelin/ceramide pathway activation and subsequent activation of ERK1/2 and DNA synthesis but did not inhibit the oxLDL-induced epidermal growth factor receptor and platelet-derived growth factor receptor activation. Exogenously added activated MMP-2 or membrane type 1-MMP-1 triggered the activation of both sphingomyelin/ceramide and ERK1/2 pathways and DNA synthesis. Conversely, suppression of MMP-2 expression in MMP-2^–/– cells or in SMCs treated by small-interference RNA also blocked both sphingomyelin/ceramide signaling and DNA synthesis.

Conclusions— Together, these data demonstrate that MMP-2 plays a pivotal role in oxLDL-induced activation of the sphingomyelin/ceramide signaling pathway and subsequent SMC proliferation. These pathways may constitute a potential therapeutic target for modulating the oxLDL-induced proliferation of SMCs in atherosclerosis or restenosis.

Key Words: cells, muscle, smooth • lipoproteins • metalloproteases • sphingomyelins • ceramides

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