In recent years repressors of cardiac hypertrophy, like glykogensynthasekinase3-beta (GSK3b), could be identified in cardiomyocytes. Some studies indicate also a potential role for matrix metalloproteinases (MMPs) in protective processes of cardiac hypertrophy. Aim of this study was to characterize MMPs as repressors of hypertrophy in cardiomyocytes. Incubation of ventricular cardiomyocytes of rat with the MMP inhibitor TAPI (50 mM) or the tissue inhibitor of MMPs, TIMP-2 ( 24 nM ), increased rate of proteinsynthesis to 128 ± 7 % or 124 ± 8 % (n=17 or 11, p<0.05 vs. control) and cross sectional area of cells to 126 ± 4 % or 117 ± 3 % (n=10 or 7, p<0.05 vs. control). In addition, inhibition of expression of the MMP component hemopexin by antisense oligonucleotides enhanced the rate of proteinsynthesis to 114 ± 5 % (n=6, p<0.05 vs. control). Inhibition of PI3K by wortmannin (10 nM) reduced the rate of proteinsynthesis under TAPI stimulation from 145 ± 11 % to 93 ± 14 % (n=8 , p<0.05). Inhibition of ERK by PD98059 (10 mM) reduced enhancement of cross sectional area under TAPI stimulation from 124 ± 4 % to 101 ± 4 % (n=6, p<0.05). Analysis of ERK activation under TAPI revealed an induction of phosphorylated ERK by 139 ± 54 % within 15 minutes (n=8, p<0.05). Under incubation of cardiomyocytes with TAPI we could show in western blots enhancement of GSK3b-Ser9- phosphorylation to 236 ± 33 % (n=9, p<0.05 vs. control) within 1 hour. This phosphorylation is indicative for an inactivation of GSK3b. To confirm these results we performed direct measurement of GSK3b activity and found a reduction of GSK3b activity upon TAPI stimulation to 62 ± 4 % within 1 h (n=3, p<0.05 vs. control). Conclusions: MMPs act in cardiomyocytes as repressors of hypertrophy. Inhibition of MMPs results in inactivation of the endogenous repressor of hypertrophy GSK3b and activates classical hypertrophic signalling pathways via PI3K and ERK.