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1 Physiology, University of Manitoba, Winnipeg, Manitoba, Canada; Institute of Cardiovascular Sciences, St. Boniface Research Centre, Winnipeg, Manitoba, Canada
2 Physiology, University of Manitoba, Winnipeg, Manitoba, Canada; Surgery, University of Manitoba, Winnipeg, Manitoba, Canada; Institute of Cardiovascular Sciences, St. Boniface Research Centre, Winnipeg, Manitoba, Canada
3 Institute of Cardiovascular Sciences, St. Boniface Research Centre, Winnipeg, Manitoba, Canada
* To whom correspondence should be addressed. E-mail: peterz{at}sbrc.ca.
Phosphatidylinositol3-kinase (PI3K) is required for 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 LY294002 was concentration- and time-dependent, with 10 µM 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 LY294002 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 MMP-2 activation is PI3K-dependent. Previous research has shown a role for both furin and MT1-MMP (MMP-14) in the activation of MMP-2. The furin inhibitor DCMK did not prevent MMP-2 activation following balloon angioplasty. In contrast, balloon angioplasty induced a significant increase in the levels of MT1-MMP, which was suppressed by LY294002. No change in MT1-MMP mRNA was observed with LY294002, since equivalent amounts of this mRNA were present in both injured and non-injured 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 following vascular injury.
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