ABSTRACT
Pathological cardiac hypertrophy is a classical hallmark of heart failure. At the molecular level, inhibition of histone deacetylase (HDAC) enzymes attenuate pathological cardiac hypertrophy in vitro and in vivo. Emodin is an anthraquinone that has been implicated in cardiac protection. However, it is not known if the cardio-protective actions for emodin are mediated through HDAC-dependent regulation of gene expression. Therefore, we hypothesized that emodin would attenuate pathological cardiac hypertrophy via inhibition of HDACs, and that these actions would be reflected in an emodin-rich food like rhubarb. In this study, we demonstrate that emodin and Turkish rhubarb containing emodin inhibit HDAC activity in vitro, with fast-on, slow-off kinetics. Moreover, we show that emodin increased histone acetylation in cardiomyocytes concomitant to global changes in gene expression; gene expression changes were similar to the well-established pan-HDAC inhibitor trichostatin A (TSA). We additionally present evidence that emodin inhibited phenylephrine (PE) and phorbol myristate acetate (PMA)-induced hypertrophy in neonatal rat ventricular myocytes (NRVMs). Lastly, we demonstrate that the cardioprotective actions of emodin are translated to an angiotensin II (Ang) mouse model of cardiac hypertrophy and fibrosis and are linked to HDAC inhibition. These data suggest that emodin blocked pathological cardiac hypertrophy, in part, by inhibiting HDAC-dependent gene expression changes.
Subject(s)
Cardiomegaly/drug therapy , Emodin/pharmacology , Histone Deacetylases/metabolism , Myocytes, Cardiac/drug effects , Rheum/chemistry , Acetylation , Angiotensin II/pharmacology , Animals , Animals, Newborn , Cardiomegaly/metabolism , Cardiotonic Agents/pharmacology , Disease Models, Animal , Female , Gene Expression/drug effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/genetics , Humans , Hydroxamic Acids/pharmacology , Male , Mice , Mice, Inbred C57BL , Myocytes, Cardiac/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
Pacific tree frog (Hyla regilla) tadpoles were collected throughout the Sierra Nevada mountain range, California, USA, in 1996 and 1997 and analyzed for the presence of polychlorinated biphenyls (PCBs) and toxaphene. Whole-tadpole sigma PCB levels ranged from 244 ng/g (wet wt) at lower elevations on the western slope to 1.6 ng/g high on the eastern slope, whereas sigma toxaphene levels ranged from 15.6 to 1.5 ng/g. Linear regression of PCB and toxaphene residue levels versus elevation indicated a significant relationship, with an r2 value of 0.33 for PCB and 0.45 for toxaphene indicating a significant elevation effect on PCB and toxaphene bioaccumulation in Sierra Nevada H. regilla. Tadpole samples from sites in east-facing versus west-facing drainage basins showed significant differences in PCB and toxaphene residue levels, suggesting the possibility of a rain-shadow effect in the long-range atmospheric transport of these contaminants to the Sierra Nevada Mountains.
