Abstract-Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix proteins. These enzymes are implicated in a variety of physiological and pathological events characterized by extracellular matrix remodeling. Recent studies suggest that MMPs may have a signaling capacity, but direct evidence supporting this concept is lacking. In the present study, we demonstrate that outside-in signals delivered by exogenous MMP-1 (interstitial collagenase) markedly increase the number of tyrosine-phosphorylated proteins in platelets. Active MMP-1 also targets ␤ 3 integrins to areas of cell contact and primes platelets for aggregation. Examination of the endogenous enzyme demonstrated that activated platelets process latent MMP-1 into its active form. Neutralization of MMP-1 activity with MMP inhibitors or specific blocking antibodies markedly attenuates agonist-induced phosphorylation of intracellular proteins, movement of ␤ 3 integrins to cell contact points, and intercellular aggregation. Key Words: matrix metalloproteinases Ⅲ platelets Ⅲ signaling Ⅲ thrombosis D ysregulated turnover of extracellular matrix (ECM) is a prominent feature of atherosclerosis and abdominal aortic aneurysm formation and of a variety of other conditions, including rheumatoid arthritis, tumor invasion and metastasis, and periodontal disease. 1-3 Experimental evidence suggests that overproduction and/or unimpeded activity of matrix metalloproteinases (MMPs) contributes to these disease processes by mediating excessive ECM destruction, thereby disrupting the balance between protein synthesis and degradation necessary for normal matrix assembly, remodeling, and repair. Pro forms of MMPs are constitutively expressed or synthesized by a number of cell types. These proenzymes are then processed to active forms. This often occurs at the cell surface, thereby focusing proteolytic events at contact points between the cell and the ECM. 2 Degradation of the ECM by MMPs links these enzymes to the complex integrated events that underlie cell migration. 4 Although the ECM is a primary target, MMPs also alter cell surface proteins, receptors, and transmembrane ECM proteins and by this mechanism regulate intercellular adhesion and signaling. 2 The identities of specific MMPs that mediate these events have been elusive, but the observations are consistent with recent evidence indicating that other metalloproteinase family members can regulate intracellular signal transduction. 2,5,6 In the present study, we demonstrate that endogenous and exogenous MMP-1 activates pathways that signal the phosphorylation of intracellular proteins, distributes ␤ 3 integrins to cell contact points, and primes platelets for aggregation. These experiments provide new evidence that MMP-1 can regulate outside-in signaling events that control cellular function and phenotype. Materials and Methods Cell IsolationWashed platelets were isolated according to protocols previously described by our laboratory. 7 The platelet pellet was resuspended at 1ϫ10 9 cells/...

Abstract-Circulating monocytes adhere to platelets and matrix proteins at sites of vascular injury, where engagement of specific surface tethering molecules mediates outside-in signaling and synthesis of gene products by the leukocytes.Here we demonstrate that interaction of isolated human monocytes with collagen induces matrix metalloproteinase-9 (MMP-9; gelatinase B) synthesis by monocytes, a process that is greatly enhanced in the presence of platelets. MMP-9 is a potent matrix degrading enzyme implicated in atherosclerotic plaque rupture, aneurysm formation, and other vascular syndromes. Synthesis of MMP-9 by monocytes is tightly regulated and synergistically increased following adhesion to collagen and platelets. Adhesion to control matrix proteins alone did not result in MMP-9 protein production and, similarly, adhesion of monocytes to platelets activated with thrombin in suspension was not sufficient to induce MMP-9 synthesis in the absence of monocyte adhesion to collagen. Interruption of intercellular contact between platelets and monocytes dramatically inhibited MMP-9 synthesis. These observations demonstrate that discrete adhesion-dependent signaling pathways govern MMP-9 synthesis by monocytes. The synthesis of MMP-9 by monocytes may be critical in vascular syndromes and other pathological processes that are dependent on dysregulated cell-cell and cell-matrix interactions. (Circ Res. 2001;89:509-516.)

Simvastatin significantly suppresses experimental aneurysm expansion and reduces protein levels of MMP-9 and nuclear factor-kappaB. Gene array analysis provides evidence that several mediators of inflammation, matrix remodeling, and oxidative stress are downregulated by simvastatin treatment. This suggests that simvastatin inhibits AAA formation by blocking the expression of certain proinflammatory genes. Simvastatin may be useful as an adjuvant therapy to suppress the growth of small aneurysms.

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