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.

Increased Medial Degradation With Pseudo-Aneurysm Formation in Apolipoprotein E–Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1

“…Our data may also indicate that other inhibitors of MMPs in the atherosclerotic lesion, such as TIMP-2, TIMP-3, and the tissue factor pathway inhibitor-2, 31 have a more essential role than TIMP-1 in the regulation of MMPs during plaque evolution. In addition, because TIMP-1 does not affect MMP-14 activity, it is possible that this proteinase could be critical in lesion remodeling through its ability to activate proMMP-2 and digest fibrillar collagens.…”

Gelatinase-mediated migration and invasion of cancer cells

“…However, the domain also contains RGD-dependent and RGD-independent recognition sites for α V β 3 and α V β 5 integrins and can regulate angiogenesis through integrinmediated signalling (Pedchenko et al, 2003). Tissue factor pathway inhibitor-2, despite being a serine protease inhibitor, can also inhibit MMPs, including the gelatinases (Herman et al, 2001).…”

Retinal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats and a sodium-iodate-induced model in rabbits

“…TFPI-2 is thought to be involved in the coagulation cascade, 13 as well as the proliferation of smooth muscle cells 14 and inhibition of matrix metalloproteinase, 15 although the mechanism of action is still unclear. It was recently reported that TFPI-2 has unique functional properties to stimulate the growth of RPE cells without the growth stimulatory functions on fibroblasts and vascular endothelial cells.…”