Curcumin and its demethoxy derivatives possess p300 HAT inhibitory activity and suppress hypertrophic responses in cardiomyocytes

Sunagawa, Yoichi; Funamoto, Masafumi; Sono, Shogo; Shimizu, Kana; Shimizu, Satoshi; Genpei, Mai; Miyazaki, Yusuke; Katanasaka, Yasufumi; Morimoto, Eriko; Ueno, Masaki; Komiyama, Maki; Kakeya, Hideaki; Wada, Hiromichi; Hasegawa, Koji; Morimoto, Tatsuya

doi:10.1016/j.jphs.2017.12.013

Cited by 31 publications

(27 citation statements)

References 29 publications

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“…It has previously been reported that the functional groups on the aromatic rings of curcumin are involved in hydrogen bonding to p300 19 . Furthermore, we previously reported that the methoxy groups at position 3 did not affect p300-HAT inhibitory activity 21 . Taken together, these findings suggest that the addition of a methoxy group or a methoxymethoxy group at position 5 is important for binding affinity to p300 via the hydrogen bond.…”

Section: Scientific Reports |mentioning

confidence: 92%

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The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice

Shimizu

Sunagawa

Funamoto

et al. 2020

Sci Rep

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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...

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Section: Scientific Reports |mentioning

confidence: 92%

“…In vitro p300-HAT assay. The in vitro p300-HAT assay was performed as described previously 21 . In brief, 5 μg of core histones from calf thymus (Worthington, USA) was incubated in HAT buffer with purified p300-HAT recombinant domain in the presence of curcumin or GO-Y030 at room temperature for 30 min.…”

Section: Methodsmentioning

confidence: 99%

The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice

Shimizu

Sunagawa

Funamoto

et al. 2020

Sci Rep

Self Cite

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“…As main molecular targets, it is noteworthy that curcumin activates the Nrf2 which leads to HO-1 induction, responsible for cytoprotective and anti-inflammatory effects against oxidative stress (Pittala et al, 2018). For example, Sunagawa et al (2018) showed that curcumin is a natural p300 histone acetyltransferase (HAT) inhibitor, while Monfoulet et al (2017) reported that curcumin is able to enhance endothelial function and to decrease the TNFa-induced monocyte adhesion in endothelial cells through NF-kB inhibition. Furthermore, Yao et al (2016) found that curcumin reduces angiotensin II type 1 receptor (AT1R) expression, thus preventing CV diseases.…”

Section: Cardioprotective Effectmentioning

confidence: 99%

Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications

et al. 2020

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Curcumin, a yellow polyphenolic pigment from the Curcuma longa L. (turmeric) rhizome, has been used for centuries for culinary and food coloring purposes, and as an ingredient for various medicinal preparations, widely used in Ayurveda and Chinese medicine. In recent decades, their biological activities have been extensively studied. Thus, this review aims to offer an in-depth discussion of curcumin applications for food and biotechnological industries, and on health promotion and disease prevention, with particular emphasis on its antioxidant, anti-inflammatory, neuroprotective, anticancer, hepatoprotective, and cardioprotective effects. Bioavailability, bioefficacy and safety features, side effects, and quality parameters of curcumin are also addressed. Finally, curcumin's multidimensional applications, food attractiveness optimization, agro

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“…Curcumin has shown protective effects in several models of CVDs via decreasing hypertension (J. Hu et al, ), atherosclerosis (Zou, Zhang, Li, Zheng, & Feng, ), cardiac hypertrophy (Sunagawa et al, ), ischemia–reperfusion (I‐R) injury (H. Liu, Wang, Qiao, & Xu, ), and diabetic cardiovascular complications (H. Chen, Yang, et al, ; C. Li et al, ). Because elevated oxidative stress and the resulting proinflammatory responses both contribute to CVDs' development and progression, curcumin's inhibitory effect on ROS generation coupled with its anti‐inflammatory properties may contribute towards its protective effect against CVDs.…”

Section: Antioxidative and Anti‐inflammatory Properties Of Curcumin Imentioning

confidence: 99%

“…Evidence has shown that curcumin can inhibit cardiomyocyte hypertrophy in cultured cardiomyocytes, as well as the onset of heart failure in hypertensive heart disease and MI rat models (Morimoto, Sunagawa, Fujita, & Hasegawa, ). A study has found that curcumin can prevent the development of cardiac hypertrophy by inhibiting p300‐specific histone acetyltransferase (HAT) activity (Sunagawa et al, ). It is reported that curcumin can exert cardioprotective effects on chronic heart failure via up‐regulating Dickkopf‐3 (Cao et al, ).…”

Section: Antioxidative and Anti‐inflammatory Properties Of Curcumin Imentioning

confidence: 99%

Curcuminoids: Implication for inflammation and oxidative stress in cardiovascular diseases

Miao

et al. 2019

Phytotherapy Research

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It has been extensively verified that inflammation and oxidative stress play important roles in the pathogenesis of cardiovascular diseases (CVDs). Curcuminoids, from the plant Curcuma longa, have three major active ingredients, which include curcumin (curcumin I), demethoxycurcumin, and bisdemethoxycurcumin. Curcuminoids have been used in traditional medicine for CVDs' management and other comorbidities for centuries. Numerous studies had delineated their anti‐inflammatory, antioxidative, and other medicinally relevant properties. Animal experiments and clinical trials have also demonstrated that turmeric and curcuminoids can effectively reduce atherosclerosis, cardiac hypertrophy, hypertension, ischemia/reperfusion injury, and diabetic cardiovascular complications. In this review, we introduce and summarize curcuminoids' molecular and biological significance, while focusing on their mechanistic anti‐inflammatory/antioxidative involvements in CVDs and preventive effects against CVDs, and, finally, discuss relevant clinical applications.

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Curcumin and its demethoxy derivatives possess p300 HAT inhibitory activity and suppress hypertrophic responses in cardiomyocytes

Cited by 31 publications

References 29 publications

The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice

The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice

Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications

Curcuminoids: Implication for inflammation and oxidative stress in cardiovascular diseases

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