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Study of MMP-2 phosphorylated forms and the effect of doxycycline

Abstract

The regulation of matrix metalloproteinases (MMP) has been studied due to the fundamental roles these zinc-endopeptidases play in diverse physiological and pathological processes. Phosphorilation is the mainly posttranslational modification in eukaryonts and has been described in recombinant MMP-2 from hamster ovarian cells and in MMP-2 from HT1080 cell-conditioned medium supernatant. The phosphorylation has been since considered as a potential modulator of MMP-2 activity. MMP-2 has already has been described in intracellular compartments and has been related to the development and plaque instability during atherosclerosis. Since atherosclerosis is a chronic inflammatory disease and MMP-2 contains potential phosphorylation sites, its possible that factors involved in the pathogenesis of atherosclerosis change the phosphorylation of MMP-2, which could be modificated by MMPs inhibitors. The aims of the study are: 1) to check whether MMP-2s phosphorylated forms occurs in hearts and aortics extracts of atherosclerotic rabbits and evaluate whether the phosphorylation may contribute to alterations in MMP-2 activity; 2) to assess whether doxycycline treatment could promote changes in MMP-2 phosphorilation status. To test these hypotheses we will induce atherosclerosis by dietary-induced hypercholesterolaemia in New Zealand rabbits, which hearts and aortic rings will be used to zymography, western blot, SDS-PAGE with Phos-Tag and fluorimetric assays. To get more phosphorylation controls, some samples will be treat with phosphatases and samples from HT1080 cell-conditioned medium supernatant will be use in these assays. (AU)

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