Hemodynamic overload in the heart can trigger maladaptive hypertrophy of cardiomyocytes. A key signaling event in this process is nuclear acetylation by histone deacetylases and p300, an intrinsic histone acetyltransferase (HAT). It has been previously shown that curcumin, a polyphenol responsible for the yellow color of the spice turmeric, possesses HAT inhibitory activity with specificity for the p300/CREB-binding protein. We found that curcumin inhibited the hypertrophy-induced acetylation and DNA-binding abilities of GATA4, a hypertrophy-responsive transcription factor, in rat cardiomyocytes. Curcumin also disrupted the p300/GATA4 complex and repressed agonist-and p300-induced hypertrophic responses in these cells. Both the acetylated form of GATA4 and the relative levels of the p300/GATA4 complex markedly increased in rat hypertensive hearts in vivo. The effects of curcumin were examined in vivo in 2 different heart failure models: hypertensive heart disease in salt-sensitive Dahl rats and surgically induced myocardial infarction in rats. In both models, curcumin prevented deterioration of systolic function and heart failure-induced increases in both myocardial wall thickness and diameter. From these results, we conclude that inhibition of p300 HAT activity by the nontoxic dietary compound curcumin may provide a novel therapeutic strategy for heart failure in humans.

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is the active ingredient of turmeric, which has a long history of being consumed as a dietary spice.1) In addition, turmeric is widely used in traditional Indian medicine to treat biliary disorders, anorexia, cough, diabetic complications, hepatic disorders, rheumatism, and sinusitis.2) Extensive investigation over the past five decades has indicated that curcumin reduces blood cholesterol, prevents low-density lipoprotein oxidation, inhibits platelet aggregation, suppresses thrombosis and myocardial infarction, suppresses symptoms associated with type 2 diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheimer's disease, inhibits human immunodeficiency virus (HIV) replication, enhances wound healing, protects against liver injury, increases bile secretion, protects from cataract formation, and protects against pulmonary toxicity and fibrosis.3-5) Evidence indicates that the divergent effects of curcumin are dependent on its pleiotropic molecular effects.In spite of these attractive properties of curcumin, information on the therapeutic efficiency of curcumin has been limited, partly due to its poor oral bioavailability. 6) Curcumin was found to be poorly soluble in water, the maximum solubility of which in aqueous buffer (pH 5.0) was reported to be as low as 11 ng/ml.7) The limited solubility of curcumin, as well as extensive systemic metabolism, could be responsible for the low bioavailability of curcumin after oral delivery. [8][9][10] In addition, curcumin in solution may be sensitive to UV light, and so marked photochemical degradation could occur under UV exposure, 11) leading to difficulty in its handling for clinical use.A number of efforts have been made to design a soluble formulation of curcumin, but no suitable delivery options have been found so far. We have developed an effective preparation of curcumin, a nano-particle colloidal dispersion, with improved oral bioavailability, and named it THER-ACURMIN. It has the following unique properties: 1) it is an effective preparation for new health care products (beverages, food, and supplements) which may be taken at a much lower dosage; 2) it is soluble in water, which is a must for an effective beverage product; 3) the preparation is highly stable in light (UV), and, therefore, can be put into transparent PET bottles; 4) it is heat-stable, including high temperature sterilization conditions; 5) the preparation has no unpleasant odor or taste.The main purpose of this study was to provide evidence to support the improved bioavailability and alcohol-toxicity-reducing effect of THERACURMIN through oral delivery. We evaluated the plasma pharmacokinetics of this new curcumin preparation and compared the results with curcumin powder after oral administration in rats and healthy human subjects. We also investigated the effect of THERACURMIN on the toxicity of alcohol following drinking. MATERIALS AND METHODS Preparation of Curcumin Powder and THERACUR-MINCurcumin powder was extracted...

A variety of stresses on the heart initiate a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and cause myocyte hypertrophy with heart failure. However, common nuclear pathways that lead to this state are unknown. A zinc finger protein, GATA-4, is one of the transcription factors that mediate changes in gene expression during myocardial-cell hypertrophy. p300 not only acts as a transcriptional coactivator of GATA-4, but also possesses an intrinsic histone acetyltransferase activity. In primary cardiac myocytes derived from neonatal rats, we show that stimulation with phenylephrine increased an acetylated form of GATA-4 and its DNA-binding activity, as well as expression of p300. A dominant-negative mutant of p300 suppressed phenylephrine-induced nuclear acetylation, activation of GATA-4-dependent endothelin-1 promoters, and hypertrophic responses, such as increase in cell size and sarcomere organization. In sharp contrast to the activation of cardiac MEK-1, which phosphorylates GATA-4 and causes compensated hypertrophy in vivo, p300-mediated acetylation of mouse cardiac nuclear proteins, including GATA-4, results in marked eccentric dilatation and systolic dysfunction. These findings suggest that p300-mediated nuclear acetylation plays a critical role in the development of myocyte hypertrophy and represents a pathway that leads to decompensated heart failure.Heart failure arises from a number of diverse primary cardiovascular disorders and is associated with significant morbidity and mortality. Therefore, elucidating the mechanisms of this disease is of clinical importance. Previous studies have demonstrated that a variety of stresses on the heart activate neuronal and hormonal factors, such as the renin-angiotensin system and factors regulating the sympathetic nervous systems. These factors initiate a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and change the pattern of gene expression associated with hypertrophy (reviewed in references 14 and 53). In order to establish appropriate therapy for heart failure, it is critical to identify a common nuclear pathway which can be targeted by pharmacological agents in the future.We have been interested in transcription factors that mediate changes in gene expression during myocardial-cell hypertrophy. A zinc finger protein, GATA-4, is one such factor and is required for transcriptional activation of cardiac genes whose expression is upregulated during myocardial-cell hypertrophy (22, 25; reviewed in reference 46). While overexpression of GATA-4 in cardiac myocytes causes hypertrophy, expression of a dominant-negative form of GATA-4 inhibits Gq protein-coupled receptor agonist-induced hypertrophy (37). During myocardial-cell hypertrophy, GATA-4 is phosphorylated at a serine residue and shows increased DNA-binding ability (38,47). Phosphorylation of cardiac GATA-4 requires activation of MEK1/extracellular signal-regulated kinase (ERK) 1/2. On the other hand, activation of MEK1 in...

The expression of endothelin-1 (ET-1) in cardiac myocytes is markedly induced during the development of heart failure in vivo and by stimulation with the ␣ 1 -adrenergic agonist phenylephrine in culture. Although recent studies have suggested a role for cardiac-specific zinc finger GATA factors in the transcriptional pathways that modulate cardiac hypertrophy, it is unknown whether these factors are also involved in cardiac ET-1 transcription and if so, how these factors are modulated during this process. Using transient transfection assays in primary cardiac myocytes from neonatal rats, we show here that the GATA element in the rat ET-1 promoter was required for phenylephrine-stimulated ET-1 transcription. Cardiac GATA-4 bound the ET-1 GATA element and activated the ET-1 promoter in a sequencespecific manner. Stimulation by phenylephrine caused serine phosphorylation of GATA-4 and increased its ability to bind the ET-1 GATA element. Inhibition of the extracellularly responsive kinase cascade with PD098059 blocked the phenylephrine-induced increase in the DNA binding ability and the phosphorylation of GATA-4. These findings demonstrate that serine phosphorylation of GATA-4 is involved in ␣ 1 -adrenergic agonist-responsive transcription of the ET-1 gene in cardiac myocytes and that extracellularly responsive kinase 1/2 activation plays a role upstream of GATA-4. Endothelin-1 (ET-1)1 was initially identified as a 21-amino acid vasoconstrictive peptide in porcine vascular endothelial cells (1). Later work showed that it acts not only as a vasoconstrictor but also as a potent growth-promoting peptide. For example, ET-1 can induce myocyte hypertrophy (2, 3) through coupling of ET receptors with G q protein. ET-1 signaling is also coupled with G i protein. Therefore, it is able to decrease intracellular cAMP levels (4). Although ET-1 is mainly produced by endothelial cells in the basal state, a number of cell types can synthesize ET-1 in response to various stimuli (5-8). ET-1 expression in cardiac myocytes is induced by myocardial stretch, angiotensin II, and norepinephrine (6 -8). Left ventricular levels of ET-1 increase markedly in close association with the deterioration of systolic function following myocardial infarction and pressure overload (9, 10). Immunohistochemical studies have demonstrated that ET-1 in the failing heart is localized in cardiac myocytes. ET receptor antagonists bosentan and BQ123 prevent the remodeling of the heart and have been shown to improve survival following myocardial infarction and pressure overload (9, 10). These findings demonstrate that up-regulated expression of ET-1 in cardiac myocytes plays a critical role in the development of heart failure in vivo. However, the molecular mechanisms leading to this up-regulation in the failing heart are unclear at present.The mechanisms regulating the transcription of the ET-1 gene have been studied in endothelial cells. The 204-bp sequences proximal to the transcription starting site is sufficient to drive high levels of expression in these...

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