Eukaryotic gene expression has mainly been studied in the context of trans-acting transcription factors and their interaction with regulatory cis-elements. Evidence is accumulating, that the higher order structure of chromatin also plays an essential role in eukaryotic gene expression. Hepatic stellate cells are the major cellular source of extracellular matrix synthesis in chronic liver diseases leading to fibrosis. We explored the antifibrogenic effect of the histone deacetylase inhibitor trichostatin A (TSA) on hepatic stellate cells in vitro. Primary hepatic stellate cells as well as activated, subcultured stellate cells were exposed to 10(-7) M-10(-9) M TSA. Collagens type I and III, and smooth muscle alpha-actin (alpha-SMA), a marker for transdifferentiation, were investigated at the protein and mRNA level by performing Northern hybridisation and quantitative immunoprecipitation. The antiproliferative effect was examined by 3H-thymidine incorporation and cell counting. Hyperacetylation of histone H4 was demonstrated by acid urea Triton-X-100 (AUT) polyacrylamide gel electrophoresis. TSA at 10(-7) M retarded the morphological changes characteristics for activation of primary stellate cells. Synthesis of collagens type I and III, and alpha-SMA was strongly inhibited at both protein and mRNA level. The proliferation rate of primary hepatic stellate cells was strongly suppressed by 10(-7) M TSA. Hyperacetylation of histone H4 showed to be maximal at 10(-7) M TSA. Primary hepatic stellate cells were more affected by TSA than subcultured stellate cells.

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Characteristics of energy metabolism in specialized muscle of bovine heart.

Characterization of the energy metabolism pattern of the specialized heart muscle of bovine heart was studied in comparison with that of the ordinary heart muscle. Mitochondrial oxygen consumption of the specialized heart muscle was significantly lower than that of the ordinary heart muscle with succinate as the substrate. On the other hand, there was no significant difference in oxygen consumption between both heart muscles with glutamate + malate as the substrates. The activity levels of succinate dehydrogenase and lactate dehydrogenase were much lower than those of the ordinary heart muscle. The isozyme pattern of LDH of the specialized heart muscle consisted of one major component of LDH-1 (H4) and that of the ordinary heart muscle consisted of two major components of LDH-1 (H4) and LDH-2 (H3M). The ratio of NADH to NAD of the specialized heart muscle was remarkably lower than that of the ordinary heart muscle. These results indicate that the specialized heart muscle depends not only upon anaerobic metabolism but also upon aerobic metabolism for its energy supply.

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