Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis
Michael P. Herman, Galina K. Sukhova, Walter Kisiel, Don Foster, Marilyn R. Kehry, Peter Libby, Uwe Schönbeck
Michael P. Herman, Galina K. Sukhova, Walter Kisiel, Don Foster, Marilyn R. Kehry, Peter Libby, Uwe Schönbeck
View: Text | PDF
Article

Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis

Abstract

Degradation of ECM, particularly interstitial collagen, promotes plaque instability, rendering atheroma prone to rupture. Previous studies implicated matrix metalloproteinases (MMPs) in these processes, suggesting that dysregulated MMP activity, probably due to imbalance with endogenous inhibitors, promotes complications of atherosclerosis. We report here that the serine proteinase inhibitor tissue factor pathway inhibitor-2 (TFPI-2) can function as an MMP inhibitor. TFPI-2 diminished the ability of the interstitial collagenases MMP-1 and MMP-13 to degrade triple-helical collagen, the primary load-bearing molecule of the ECM within human atheroma. In addition, TFPI-2 also reduced the activity of the gelatinases MMP-2 and MMP-9. In contrast to the “classical” tissue inhibitors of MMPs (TIMPs), TFPI-2 expression in situ correlated inversely with MMP levels in human atheroma. TFPI-2 colocalized primarily with smooth muscle cells in the normal media as well as the plaque’s fibrous cap. Conversely, the macrophage-enriched shoulder region, the prototypical site of matrix degradation and plaque rupture, stained only weakly for TFPI-2 but intensely for gelatinases and interstitial collagenases. Evidently, human mononuclear phagocytes, an abundant source of MMPs within human atheroma, lost their ability to express this inhibitor during differentiation in vitro. These findings establish a new, anti-inflammatory function of TFPI-2 of potential pathophysiological significance for human diseases, including atherosclerosis.

Authors

Michael P. Herman, Galina K. Sukhova, Walter Kisiel, Don Foster, Marilyn R. Kehry, Peter Libby, Uwe Schönbeck

×

Figure 6

Options: View larger image (or click on image) Download as PowerPoint
TFPI-2 expression is diminished in the shoulder region of human atherosc...
TFPI-2 expression is diminished in the shoulder region of human atherosclerotic plaques. (a, b) Shown are single-wavelength filter photomicrographs (×10) of cryostat sections from atherosclerotic carotid atheroma applied to double-immunofluorescence labeling to colocalize (a) MMP-2 or (b) MMP-9 (both red) with TFPI-2 (green) within the SMC-enriched fibrous cap. (c) Triple-immunofluorescence labeling colocalized MMP-2 (red) with TFPI-2 (green) within the plaque’s shoulder region (left: ×4, right: ×10). Nuclei are stained in blue. High-magnification photomicrographs (×40) demonstrated differential expression of (d) MMP-1 or (e) MMP-13 (both red) with TFPI-2 (green) in SMC-enriched (left) or MØ-enriched (right) areas of human atheroma; nuclei are stained in blue. (f) Protein extracts from frozen tissue of nonatherosclerotic carotid arteries (Normal), as well as carotid plaques dichotomized into lesions displaying features associated with either stable (Fibrous) or vulnerable (Athero) plaques, were analyzed by Western blotting employing α–TIMP-1 (top), –TIMP-2 (middle), or –TFPI-2 (bottom). Analysis of five normal arteries, five fibrous and seven atheromatous surgical specimens of atheroma from different donors showed similar results.