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- Corrigendum (July 2009)
Currying favor for the heart
Jonathan A. Epstein
Department of Cell and Developmental Biology, Cardiovascular Institute, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Address correspondence to: Jonathan A. Epstein, Department of Cell and Developmental Biology, Cardiovascular Institute, and Institute for Regenerative Medicine, University of Pennsylvania, 1154 BRB II, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-8731; Fax: (215) 573-2094; E-mail: epsteinj@mail.med.upenn.edu.
Find articles by Epstein, J. in: JCI | PubMed | Google Scholar
Published February 21, 2008 - More info
J Clin Invest. 2008;118(3):850–852. https://doi.org/10.1172/JCI34650.
© 2008 The American Society for Clinical Investigation
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Abstract
Chromatin remodeling, particularly histone acetylation, plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. We hypothesized that curcumin, a natural polyphenolic compound abundant in the spice turmeric and a known suppressor of histone acetylation, would suppress cardiac hypertrophy through the disruption of p300 histone acetyltransferase–dependent (p300-HAT–dependent) transcriptional activation. We tested this hypothesis using primary cultured rat cardiac myocytes and fibroblasts as well as two well-established mouse models of cardiac hypertrophy. Curcumin blocked phenylephrin-induced (PE-induced) cardiac hypertrophy in vitro in a dose-dependent manner. Furthermore, curcumin both prevented and reversed mouse cardiac hypertrophy induced by aortic banding (AB) and PE infusion, as assessed by heart weight/BW and lung weight/BW ratios, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that curcumin abrogated histone acetylation, GATA4 acetylation, and DNA-binding activity through blocking p300-HAT activity. Curcumin also blocked AB-induced inflammation and fibrosis through disrupting p300-HAT–dependent signaling pathways. Our results indicate that curcumin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through suppression of p300-HAT activity and downstream GATA4, NF-κB, and TGF-β–Smad signaling pathways.
Authors
Hong-Liang Li, Chen Liu, Geoffrey de Couto, Maral Ouzounian, Mei Sun, Ai-Bing Wang, Yue Huang, Cheng-Wei He, Yu Shi, Xin Chen, Mai P. Nghiem, Youan Liu, Manyin Chen, Fayez Dawood, Masahiro Fukuoka, Yuichiro Maekawa, Liyong Zhang, Andrew Leask, Asish K. Ghosh, Lorrie A. Kirshenbaum, Peter P. Liu
Abstract
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.
Authors
Tatsuya Morimoto, Yoichi Sunagawa, Teruhisa Kawamura, Tomohide Takaya, Hiromichi Wada, Atsushi Nagasawa, Masashi Komeda, Masatoshi Fujita, Akira Shimatsu, Toru Kita, Koji Hasegawa
Epigenetics is a term used to describe features of DNA packaging and assembly that modify cellular process and are stably maintained when cells divide, but do not involve changes in DNA sequence. DNA is maintained within the nucleus in an ordered and dynamic structure in association with other proteins, including histones. The complex of DNA and associated proteins is known as chromatin, and an exciting area of active research involves the epigenetic regulation of chromatin structure by enzymes that modify histones. Among these enzymes are those that add or remove acetyl groups on lysine tails of histones. Enzymes that remove acetyl groups are called histone deacetylases (HDACs), and those reactions are reversed by histone acetyl transferases (HATs), which include p300 and CREB-binding protein (CBP). In general, HDACs act as transcriptional repressors, since removal of acetyl groups allows the chromatin to pack more tightly, and access of transcription factors to promoters is restricted. Conversely, HATs tend to function as activators of gene expression.
HDACs have recently been implicated as important regulators of cardiac homeostasis (1). There are at least 11 mammalian HDACs that compose the so-called class 1 and class 2 families, in addition to more distantly related families (2). Inactivation of some of the class 2 HDACs in mice results in cardiac hypertrophy and subsequent heart failure (1, 3, 4). On the other hand, inactivation of a class 1 HDAC, HDAC2, results in resistance to cardiac hypertrophy (5), which suggests that class 1 and class 2 HDACs may play opposing roles (6). Interestingly, chemical HDAC inhibitors, which block both classes, tend to block hypertrophic responses (6–8). In this issue of the JCI, 2 papers examine the effects of curcumin on the heart and conclude that this commonly available spice blocks HAT activity and prevents cardiac hypertrophy and failure in rodent models (9, 10).
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Translating animal studies to clinical practice calls for caution
The studies by Li et al. (9) and Morimoto et al. (10) suggest that curcumin may have beneficial effects on the heart in the setting of pressure overload or after myocardial infarction. However, translation of these data to humans is not clear cut, and extrapolation should be attempted with caution. Despite numerous interventions that prove efficacious in rodent models after myocardial infarction, for example, few have proven successful in clinical trials (23). Likewise, prior claims of the beneficial effects of curcumin in other settings, largely advanced on the basis of in vitro and animal studies, have proven disappointing (11, 12). The mechanism of action of curcumin in the heart remains unclear. While the correlations regarding p300 activity, GATA4 acetylation, and inflammatory pathways are intriguing, additional studies will be necessary to determine which, if any, of these explanations satisfy tests of necessity and sufficiency in vitro and in vivo. These results may provide more specific therapeutic targets and may provide relevant bioassays with which to monitor clinical trials.
If inhibition of p300-HAT activity proves to be the critical mechanism by which curcumin modulates cardiac responses to stress, still more questions will need to be addressed. How can an inhibitor of HDAC activity (such as trichostatin A; refs. 6–8) and an inhibitor of HAT activity (like curcumin) both block hypertrophic responsiveness, when HDAC and HAT pathways oppose one another? Are the same gene expression changes being affected by apparently opposing chemical inhibitors? Is one class of inhibitor blocking a prohypertrophic pathway, while the other is activating a distinct antihypertrophic or protective pathway (Figure 1)? Given the low incidence of reported side effects in animal models and in human trials with HDAC and HAT inhibitors (2, 11, 24), one wonders whether we truly understand the nature and extent of gene expression controlled by these “global” regulators. Do redundant and feedback mechanisms limit the global effects of these inhibitors? The answers to these questions may provide new therapeutic targets for heart failure and may also refine our understanding of the mechanisms by which chromatin remodeling complexes function inside the cell.
Figure 1Curcumin can block cardiac hypertrophy in isolated cells and animal models, but the mechanism of action is unclear. This model depicts possible actions (indicated by question marks) of curcumin, including direct inhibition of p300-HAT activity and inhibition of p300 acetylation of GATA4, MEF2C, or NF-κB. p300 functions with GATA4 and MEF2C to activate hypertrophic pathways and may function with NF-κB to drive pathways important in cardiac fibrosis. Class 2 HDACs interfere with the action of MEF2C and oppose cardiac hypertrophy, while class 1 HDACs have been postulated to inhibit antihypertrophic or protective pathways. Curcumin could potentially inhibit the ability of p300 or other factors to activate class 1 HDACs. In this issue of the JCI, Li et al. (9) and Morimoto et al. (10) demonstrate that curcumin can block cardiac hypertrophy in rodent models. Correlative data suggests that possible mechanisms of action may include inhibition of p300-HAT activity and/or inhibition of GATA4 acetylation with subsequent alterations in GATA4 activity and recruitment of p300.
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