Caffeic acid ethanolamide prevents cardiac dysfunction through sirtuin dependent cardiac bioenergetics preservation

Journal of Biomedical Science, Sep 2015

Background Cardiac oxidative stress, bioenergetics and catecholamine play major roles in heart failure progression. However, the relationships between these three dominant heart failure factors are not fully elucidated. Caffeic acid ethanolamide (CAEA), a synthesized derivative from caffeic acid that exerted antioxidative properties, was thus applied in this study to explore its effects on the pathogenesis of heart failure. Results In vitro studies in HL-1 cells exposed to isoproterenol showed an increase in cellular and mitochondria oxidative stress. Two-week isoproterenol injections into mice resulted in ventricular hypertrophy, myocardial fibrosis, elevated lipid peroxidation, cardiac adenosine triphosphate and left ventricular ejection fraction decline, suggesting oxidative stress and bioenergetics changes in catecholamine-induced heart failure. CAEA restored oxygen consumption rates and adenosine triphosphate contents. In addition, CAEA alleviated isoproterenol-induced cardiac remodeling, cardiac oxidative stress, cardiac bioenergetics and function insufficiency in mice. CAEA treatment recovered sirtuin 1 and sirtuin 3 activity, and attenuated the changes of proteins, including manganese superoxide dismutase and hypoxia-inducible factor 1-α, which are the most likely mechanisms responsible for the alleviation of isoproterenol-caused cardiac injury Conclusion CAEA prevents catecholamine-induced cardiac damage and is therefore a possible new therapeutic approach for preventing heart failure progression.

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Caffeic acid ethanolamide prevents cardiac dysfunction through sirtuin dependent cardiac bioenergetics preservation

Lee et al. Journal of Biomedical Science Caffeic acid ethanolamide prevents cardiac dysfunction through sirtuin dependent cardiac bioenergetics preservation Shih-Yi Lee 0 1 2 Hui-Chun Ku 0 Yueh-Hsiung Kuo 4 5 Kai-Chien Yang 0 Ping-Chen Tu 5 His-Lin Chiu 3 Ming-Jai Su 0 0 Institute of Pharmacology, College of Medicine, National Taiwan University , No.1, Sec.1, Jen-Ai Road, Taipei 10051 , Taiwan 1 Mackay Junior College of Medicine , Nursing, and Management, Taipei , Taiwan 2 Division of Pulmonary and Critical Care Medicine, Mackay Memorial Hospital , Taipei , Taiwan 3 Department of Chemistry, National Taiwan University , Taipei , Taiwan 4 Department of Biotechnology, Asia University , Taichung , Taiwan 5 Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University , Taichung , Taiwan Background: Cardiac oxidative stress, bioenergetics and catecholamine play major roles in heart failure progression. However, the relationships between these three dominant heart failure factors are not fully elucidated. Caffeic acid ethanolamide (CAEA), a synthesized derivative from caffeic acid that exerted antioxidative properties, was thus applied in this study to explore its effects on the pathogenesis of heart failure. Results: In vitro studies in HL-1 cells exposed to isoproterenol showed an increase in cellular and mitochondria oxidative stress. Two-week isoproterenol injections into mice resulted in ventricular hypertrophy, myocardial fibrosis, elevated lipid peroxidation, cardiac adenosine triphosphate and left ventricular ejection fraction decline, suggesting oxidative stress and bioenergetics changes in catecholamine-induced heart failure. CAEA restored oxygen consumption rates and adenosine triphosphate contents. In addition, CAEA alleviated isoproterenol-induced cardiac remodeling, cardiac oxidative stress, cardiac bioenergetics and function insufficiency in mice. CAEA treatment recovered sirtuin 1 and sirtuin 3 activity, and attenuated the changes of proteins, including manganese superoxide dismutase and hypoxia-inducible factor 1-α, which are the most likely mechanisms responsible for the alleviation of isoproterenol-caused cardiac injury Conclusion: CAEA prevents catecholamine-induced cardiac damage and is therefore a possible new therapeutic approach for preventing heart failure progression. Bioenergetics; Caffeic acid; Heart failure; Sirtuin - Background Heart failure (HF) remains a major cause of death in developed nations [1]. It is a complex and multi-causal syndrome characterized by cardiac dysfunction [2–6]. Evidence has shown that catecholamine, oxidative stress and bioenergetic insufficiency contribute to the pathogenesis of HF [7–13]. The increase in sympathetic tone in HF is supposed to compensate for cardiac dysfunction; however, a previous study found that the patients with higher plasma catecholamine concentrations had poorer outcomes [14]. A synthetic catecholamine, isoproterenol (ISO), has also been widely used to induce oxidative stress HF, displaying cardiac remodeling, dysfunction, and bioenergetics insufficiency [15–17]. These observations imply that catecholamine released to counterbalance the cardiac dysfunction could further result in myocardial oxidative injury and bioenergetics impairment in HF. Mitochondria are responsible for oxidative phosphorylation. Adenosine triphosphate (ATP) is produced from the electron transport chain (ETC) which supplies energy for well-perfused hearts [12, 18, 19]. On the other hand, reactive oxygen species (ROS) leaking from impaired ETC in failing myocardium contributes to mitochondrial and cellular oxidative stress, further deteriorating cardiac bioenergetics [9, 10, 13, 18, 20–29]. Accordingly, amelioration of mitochondrial oxidative stress has been considered as a possible resolution to © 2015 Lee et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. heart failure [23, 26]. Agents that correct impaired ETC can reduce ROS leakage from mitochondria [30, 31]. Modulation of the cellular oxidative alternation is another possible therapeutic modality [31, 32] and attenuating mitochondrial oxidative stress is yet another [33]. Sirtuins (SIRTs) are family of class III histone deacetylases, which require NAD+ to deacetylate histone and nonhistone lysines [34]. Mammals contain seven sirtuins, SIRT1–7 [35]. SIRT1 and SIRT3 are highly expressed in the nucleus/cytoplasm and mitochondria (...truncated)


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Shih-Yi Lee, Hui-Chun Ku, Yueh-Hsiung Kuo, Kai-Chien Yang, Ping-Chen Tu, His-Lin Chiu, Ming-Jai Su. Caffeic acid ethanolamide prevents cardiac dysfunction through sirtuin dependent cardiac bioenergetics preservation, Journal of Biomedical Science, 2015, pp. 80, 22, DOI: 10.1186/s12929-015-0188-1