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Erschienen in: Cardiovascular Toxicology 10-11/2022

05.08.2022

Alpha-Lipoic Acid Protects Against Doxorubicin-Induced Cardiotoxicity by Regulating Pyruvate Dehydrogenase Kinase 4

verfasst von: Fangxiao Gong, Jun Jin, Hengjie Li, Hui Mao

Erschienen in: Cardiovascular Toxicology | Ausgabe 10-11/2022

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Abstract

As a widely used anti-tumor anthracycline, the accumulation of Doxorubicin (DOX) in body causes irreparable cardiomyocyte damage and therefore is limited in clinical application. Strategies to prevent from DOX-associated cardiotoxicity are urgent for patients who undergo DOX-based chemotherapy. Since oxidative stress injury being the major reason for myocardial toxicity of DOX, here we demonstrated that, Alpha-lipoic acid (ALA), which is a reductive agent, plays a cardioprotective role in attenuating DOX-induced cardiotoxicity by inhibiting pyruvate dehydrogenase kinase 4 (PDK4) expression. In vivo, the beneficial effect of ALA was evidenced by increased survival rate, mechanical contraction, and oxidative phosphorylation, while decreased reactive oxidative species (ROS) and apoptosis. In vitro, PDK4 overexpression remarkably increased DOX-induced apoptosis and ROS production in H9C2 cells. Notably, the protective effect of ALA was abrogated by PDK4 overexpression. We further used PDK4 knockout mice to identify the role of PDK4 in DOX-induced cardiotoxicity. Results elicited that PDK4 deficiency showed a consistent effect in protecting DOX cardiotoxicity as ALA treatment, which was evidenced by restored redox homeostasis and mitochondrial metabolism, finally inhibited myocardial injury. In conclusion, the cardioprotective role of ALA against DOX cardiotoxicity was dependent on PDK4-mediated regulation of oxidative stress and mitochondria metabolism.

Graphical abstract

Literatur
19.
Metadaten
Titel
Alpha-Lipoic Acid Protects Against Doxorubicin-Induced Cardiotoxicity by Regulating Pyruvate Dehydrogenase Kinase 4
verfasst von
Fangxiao Gong
Jun Jin
Hengjie Li
Hui Mao
Publikationsdatum
05.08.2022
Verlag
Springer US
Erschienen in
Cardiovascular Toxicology / Ausgabe 10-11/2022
Print ISSN: 1530-7905
Elektronische ISSN: 1559-0259
DOI
https://doi.org/10.1007/s12012-022-09766-2

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