Dehydroandrographolide ameliorates doxorubicin-mediated cardiotoxicity by regulating autophagy through the mTOR-TFEB pathway

• Published in: Chemico-biological interactions Vol. 399; p. 111132
• Main Authors: Duan, Yongzhen, Huang, Peixian, Sun, Lu, Wang, Panxia, Cai, Yi, Shi, Tingting, Li, Yuliang, Zhou, Yuhua, Yu, Shanshan
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 25-08-2024
• Subjects: Animals; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Cardiotoxicity; Cardiotoxicity - prevention & control; Dehydroandrographolide; Diterpenes - chemistry; Diterpenes - pharmacology; Doxorubicin; Doxorubicin - toxicity; Male; Mice; Mice, Inbred C57BL; mTOR; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; TFEB; TOR Serine-Threonine Kinases - metabolism; mTOR; TFEB; Cardiotoxicity; Doxorubicin; Autophagy; Dehydroandrographolide
• ISSN: 0009-2797; 1872-7786; 1872-7786
• DOI: 10.1016/j.cbi.2024.111132

The clinical application of doxorubicin (DOX) was limited by the serious cardiotoxicity. The traditional Chinese medicine Andrographis paniculata and its principal active component (Dehydroandrographolide, DA) have been well known for their diverse cardiovascular protective effects. However, the effects of DA on DOX-induced cardiotoxicity (DIC) were still unknown. In this study, we evaluated the effects and revealed the potential mechanisms of DA on DIC both in vivo and in vitro. The effects of DA on DIC were systematically assessed by echocardiography and histological assays. Western blot and flow cytometry were used to measure apoptosis of cardiomyocytes. Transmission electron microscopy and StubRFP-SensGFP-LC3 lentivirus were further used to assay autophagic flux. Our results showed that DA administration significantly improved cardiac function and attenuated DOX-induced cardiomyocyte apoptosis. Mechanically, DA restored autophagic flux and lysosome functions via inhibiting DOX-induced mTOR signal pathway activation and increasing the translocation of TFEB to the nucleus. However, activation of mTOR or knockdown of TFEB significantly inhibited the protective effects of DA against DIC by impacting lysosomal functions and autophagic flux. In conclusion, our results revealed that DA might be a potential cardioprotective agent against DIC.
The graphical abstract. Schematic diagram of the protective effects of DA on DIC. DA inhibited the phosphorylation of TFEB by mTOR and promoted the expression of TFEB nucleus and downstream autophagy and lysosome-related genes, subsequently improving lysosomal functions and autophagic flux to alleviate DIC. [Display omitted]
•DA effectively attenuates DIC and suppresses cardiomyocyte apoptosis both in vivo and in vitro.•DA improves autophagic flux by enhancing lysosomal functions.•DA regulates autophagic flux through the mTOR-TFEB signal pathway.