In recent years repressors of cardiac hypertrophy, like glykogensynthasekinase3-beta (GSK3ß), 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) increased rate of proteinsynthesis to 128 7% (n=17, p<0.05 vs. control) and cross sectional area of cells to 126 4% (n=10, p<0.05 vs. control). Also the MMP3 inhibitor III (50 mM) increased the rate of proteinsynthesis to 107 2.2% (n=5, p<0.05 vs. control). In addition, we could show that 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). To analyze signal transduction of TAPI induced hypertrophy we used inhibitors of transcription (actinomycin D, 5 mg/ml) or translation (cycloheximid, 20 mg/ml). Both substances reduced enlargement of cross sectional area under TAPI stimulation from 124 13.7% to 108.6 10.7% or to 110.3 19.3% (n=13, p<0.05). Inhibition of the classic hypertrophic signal molecule PI3K by LY294002 (10 mM) or wortmannin (10 nM) also prevented TAPI induced hypertrophic growth. Under incubation of cardiomyocytes with TAPI we could show in western blots enhancement of GSK3ß-Ser9-phosphorylation to 236 33% (n=9, p<0.05 vs. control) within 1 hour. This phosphorylation is indicative for an inactivation of GSK3ß via TAPI.

Conclusions: 

MMPs act in cardiomyocytes as repressors of hypertrophy. Inhibition of MMPs results in inactivation of the endogenous repressor of hypertrophy GSK3ß and activates classical hypertrophic signalling pathways via PI3K.