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
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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
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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)