Abstract
Honokiol is a key component of a medicinal herb, Magnolia bark. Honokiol possesses potential pharmacological benefits for many disease conditions, especially cancer. Recent studies demonstrate that Honokiol exerts beneficial effects on cardiac hypertrophy and doxorubicin (Dox)-cardiotoxicity via deacetylation of mitochondrial proteins. However, the effects and mechanisms of Honokiol on cardiac mitochondrial respiration remain unclear. In the present study, we investigate the effect of Honokiol on cardiac mitochondrial respiration in mice subjected to Dox treatment. Oxygen consumption in freshly isolated mitochondria from mice treated with Honokiol showed enhanced mitochondrial respiration. The Dox-induced impairment of mitochondrial respiration was less pronounced in honokiol-treated than control mice. Furthermore, Luciferase reporter assay reveals that Honokiol modestly increased PPARγ transcriptional activities in cultured embryonic rat cardiomyocytes (H9c2). Honokiol upregulated the expression of PPARγ in the mouse heart. Honokiol repressed cardiac inflammatory responses and oxidative stress in mice subjected to Dox treatment. As a result, Honokiol alleviated Dox-cardiotoxicity with improved cardiac function and reduced cardiomyocyte apoptosis. We conclude that Honokiol protects the heart from Dox-cardiotoxicity via improving mitochondrial function by not only repressing mitochondrial protein acetylation but also enhancing PPARγ activity in the heart. This study further supports Honokiol as a promising therapy for cancer patients receiving Dox treatment.
Highlights
Doxorubicin (Dox) is one of the anthracyclines that are effective anti-cancer drugs extensively used in clinical practice
The Maximal coupling respiration in cardiac mitochondria isolated from the Dox + Honokiol group was upregulated compared with vehicle control, and Honokiol treatment prevented the Dox-induced downregulation (Fig. 2C)
Honokiol raised basal respiratory control ratios (RCR), and attenuated Dox-induced RCR downregulation (Fig. 2F). These results demonstrate for the first time that Honokiol promotes cardiac mitochondrial respiration and improves impaired cardiac mitochondrial respiration by Dox in mice
Summary
Doxorubicin (Dox) is one of the anthracyclines that are effective anti-cancer drugs extensively used in clinical practice. A series of studies have proposed that reactive oxygen species (ROS) induced-mitochondrial damage was one of the major factors responsible for the cardiotoxic effect of Dox[3,4]. Dox-induced cardiac injury has been shown to correlate with mitochondrial dysfunction[5], oxidative stress[6], impaired DNA and protein synthesis, myofibril degeneration, and cardiomyocyte apoptosis[7]. A previous study showed that Honokiol protects rat heart mitochondria against lipid peroxidation[16]. It remains unknown if Honokiol affects www.nature.com/scientificreports/. We focus on investigating how Honokiol treatment protects the mouse heart from Dox-induced mitochondrial dysfunction, oxidative stress, and inflammation via activating PPARγ
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