Article

Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent-expression of MTI-MMP

Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada
AJP Heart and Circulatory Physiology (Impact Factor: 4.01). 01/2005; 287(6):H2861-70. DOI: 10.1152/ajpheart.00230.2004
Source: PubMed

ABSTRACT Phosphatidylinositol 3-kinase (PI3K) is required for smooth muscle cell (SMC) proliferation. This study reports that inhibitors of PI3K also prevent SMC migration and block neointimal hyperplasia in an organ culture model of restenosis. Inhibition of neointimal formation by LY-294002 was concentration and time dependent, with 10 muM yielding the maximal effect. Continuous exposure for at least the first 4-7 days of culture was essential for significant inhibition. To assess the role of matrix metalloproteinases (MMPs) in this process, we monitored MMP secretion by injured vessels in culture. Treatment with LY-294002 selectively reduced active MMP-2 in media samples according to zymography and Western blot analysis without concomitant changes in latent MMP-2. Parallel results with wortmannin indicate that MMP-2 activation is PI3K dependent. Previous research has shown a role for both furin and membrane-type 1 (MT1)-MMP (MMP-14) in the activation of MMP-2. The furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone did not prevent MMP-2 activation after balloon angioplasty. In contrast, balloon angioplasty induced a significant increase in the levels of MT1-MMP, which was suppressed by LY-294002. No change in MT1-MMP mRNA was observed with LY-294002, because equivalent amounts of this mRNA were present in both injured and noninjured vessels. These results implicate PI3K-dependent regulation of MT1-MMP protein synthesis and subsequent activation of latent MMP-2 as critical events in neointimal hyperplasia after vascular injury.

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    • "Furthermore, signaling pathways involved in the mechanism of preconditioning influence the expression or activation of MMPs; e.g., activation of protein kinase C-␨ and -␪ subtypes increases expression of MMP-2 in rat cardiac fibroblast culture (Xie et al., 2004). Phosphatidylinositol 3-ki- nase-dependent up-regulation of membrane-type 1-MMP expression modulates MMP-2 activity in injured pig coronary arteries (Zahradka et al., 2004). We have previously shown that preconditioning inhibits ischemia-induced activation and release of MMP-2 into the perfusate in rat hearts (Lalu et al., 2002); however, it is not known if MMPs and their endogenous inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs), play a role in cardioprotection produced by preconditioning. "
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