Curcumin is a naturally occurring p300-histone acetyltransferase (p300-HAT) inhibitor that suppresses cardiomyocyte hypertrophy and the development of heart failure in experimental animal models. To enhance the therapeutic potential of curcumin against heart failure, we produced a series of synthetic curcumin analogues and investigated their inhibitory activity against p300-HAT. The compound with the strongest activity was further evaluated to determine its effects on cardiomyocyte hypertrophy and pressure overload-induced heart failure in mice. We synthesised five synthetic curcumin analogues and found that a compound we have named GO-Y030 most strongly inhibited p300-HAT activity. Furthermore, 1 μM GO-Y030, in a manner equivalent to 10 µM curcumin, suppressed phenylephrineinduced hypertrophic responses in cultured cardiomyocytes. In mice undergoing transverse aortic constriction surgery, administration of GO-Y030 at a mere 1% of an equivalently-effective dose of curcumin significantly attenuated cardiac hypertrophy and systolic dysfunction. In addition, this low dose of GO-Y030 almost completely blocked histone H3K9 acetylation and eliminated left ventricular fibrosis. A low dose of the synthetic curcumin analogue GO-Y030 effectively inhibits p300-HAT activity and markedly suppresses the development of heart failure in mice.open Scientific RepoRtS | (2020) 10:7172 | https://doi.org/10.1038/s41598-020-64207-w www.nature.com/scientificreports www.nature.com/scientificreports/ vivo, when transgenic mice overexpressing intact p300 in the heart undergo myocardial infarction surgery, they show significantly more progressive LV remodeling than wild-type mice undergoing the same surgery. However, when transgenic mice overexpressing mutant p300 that lacks HAT activity in the heart undergo the surgery, their degree of LV remodelling is similar to that of the wild-type mice 7 . These findings indicate that the HAT activity of p300 plays a key role in LV remodelling and systolic dysfunction, suggesting that this activity may be a target for heart failure treatment.Curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) is a polyphenol derived from Curcuma longa. It is reported to have a variety of functions, including anticancer, antioxidant, and anti-inflammatory activities 8-10 . Additionally, Balasubramanyam et al. reported that curcumin inhibits p300-specific HAT activity 11 . We previously found both that curcumin suppresses cardiomyocyte hypertrophy by inhibiting the acetylation of GATA4 and histones, and that the oral administration of curcumin at a dose of 50 mg/kg prevents the development of heart failure in rat models of hypertension and myocardial infarction 12,13 . Curcumin is a natural compound and is now widely used as a dietary supplement 14,15 . However, to develop a novel drug for heart failure therapy in the clinical setting, it is necessary to synthesise novel curcumin analogues which have much stronger activity than natural curcumin.In the present study, we examined structure-acti...

Previous studies have shown that green tea catechins (GTCs) have beneficial effects on obesity and metabolic syndromes. In this study, we prepared kosen-cha from green tea using high pressure extraction, to reduce the astringent taste of the green tea. We identified a large quantity of polymerized GTCs in kosen-cha. To investigate the effects of kosen-cha containing polymerized GTCs in obese Japanese patients, we designed an open-label pilot study in which 6 obese subjects (body mass index (BMI) >25 kg/m 2) were administered kosen-cha (5 g/L/d) for 12 weeks. Body composition, serum lipids, insulin resistance, vascular functions, and cardiac hypertrophy were measured before and 12 weeks after kosen-cha administration. Kosen-cha showed no significant adverse effects on the patients. Body weights, BMI, waist circumferences, serum triglyceride (TG) levels, and homeostasis model assessment as an index of insulin resistance (HOMA-IR) levels were significantly decreased after the 12 weeks of administration. Flow-mediated dilation (FMD) (p 0.0214), brachial-ankle pulse wave velocity (baPWV)(p 0.0141), left ventricular mass indexes (p 0.0120), and plasma brain natriuretic peptide (BNP) (p 0.0144) were significantly improved. Overall, kosen-cha reduced obesity and improved insulin resistance, vascular function, and cardiac hypertrophy, indicating its preventive potential in obesity and metabolic syndrome.

We found that curcumin, a p300 histone acetyltransferase (HAT) inhibitor, prevents cardiac hypertrophy and systolic dysfunction at the stage of chronic heart failure in Dahl salt-sensitive rats (DS). It is unclear whether curcumin suppresses the development of hypertension-induced left ventricular hypertrophy (LVH) with a preserved ejection fraction. Therefore, in this study, we randomized DS (n = 16) and Dahl salt-resistant (DR) rats (n = 10) at 6 weeks of age to either curcumin or vehicle groups. These rats were fed a high-salt diet and orally administrated with 50 mg/kg/d curcumin or its vehicle for 6 weeks. Both curcumin and vehicle treatment groups exhibited similar degrees of high-salt diet-induced hypertension in DS rats. Curcumin significantly decreased hypertension-induced increase in posterior wall thickness and LV mass index, without affecting the systolic function. It also significantly reduced hypertension-induced increases in myocardial cell diameter, perivascular fibrosis and transcriptions of the hypertrophy-response gene. Moreover, it significantly attenuated the acetylation levels of GATA4 in the hearts of DS rats. A p300 HAT inhibitor, curcumin, suppresses the development of hypertension-induced LVH, without affecting blood pressure and systolic function. Therefore, curcumin may be used for the prevention of development of LVH in patients with hypertension.

Histone acetylation by epigenetic regulators has been shown to activate the transcription of hypertrophic response genes, which subsequently leads to the development and progression of heart failure. However, nothing is known about the acetylation of the histone tail and globular domains in left ventricular hypertrophy or in heart failure. The acetylation of H3K9 on the promoter of the hypertrophic response gene was significantly increased in the left ventricular hypertrophy stage, whereas the acetylation of H3K122 did not increase in the left ventricular hypertrophy stage but did significantly increase in the heart failure stage. Interestingly, the interaction between the chromatin remodeling factor BRG1 and p300 was significantly increased in the heart failure stage, but not in the left ventricular hypertrophy stage. This study demonstrates that stage-specific acetylation of the histone tail and globular domains occurs during the development and progression of heart failure, providing novel insights into the epigenetic regulatory mechanism governing transcriptional activity in these processes.

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