The heart responds to a variety of extrinsic and intrinsic stress stimuli by hypertrophic growth. Modulation of myocardial growth is considered as a potential approach in the prevention and treatment of heart failure [1]. Recent studies have shown that histone acetyltransferases (HATs) and histone deacetylases (HDACs) participate in the regulation of genes that are pivotal for the hypertrophic response of the heart. Type I HDACs hereby favour gene expression by deacetylating histone tails resulting in relaxation of the chromatin structure. In vivo studies indicate that pharmacological inhibition of HDAC activity blunts hypertrophic growth. The aim of our study is therefore i) to establish a fast method for the determination of HDAC activity and ii) to identify potent and natural product-based inhibitors of HDAC activity. A fluorimetric enzyme assay was established to investigate HDAC activity and its modulation by different natural compounds. Nuclear extracts from human umbilical vein endothelial cells (HUVECs) and rat vascular smooth muscle cells (VSMCs) served as source of HDAC protein. Natural test compounds were selected according to their structural relationship to known HDAC inhibitors. The initial results showed that compounds such as several isoflavones, anthraderivates and capsaicines have a potential to inhibit histone deacetylase activity, although only at micromolar concentration. IC50 values were determined for aloin (150µM), for sennosides A and B (180µM and 220µM) and capsaicine (400µM). Further approach is to find potent histone deacetylase inhibitors at nanomolar concentration.
Acknowledgements: We are grateful to Dr. Dan Sorescu, Emory University, Division of Cardiology, Atlanta GA, USA, for helpful discussions.
References: [1] Frey, N. et al. (2003) Annual Review of Physiology 65, 45–79
