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A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Astragaloside IV Alleviates Doxorubicin-Induced Cardiotoxicity by Inhibiting Cardiomyocyte Pyroptosis through the
Wencong Tian1, Ping Zhang2, Lei Yang3
1Department of General Surgery, Tianjin Union Medical Center, Tianjin 300122, P. R. China.
Abstract:
Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug used to treat a wide spectrum of tumors. However, its clinical application is limited due to cardiotoxic side effects. Astragaloside IV (AS IV), one of the major compounds present in aqueous extracts of Astragalus membranaceus, possesses potent cardiovascular protective properties, but the underlying molecular mechanisms are unclear. Thus, the aim of this study was to investigate the effect of AS IV on DOX-induced cardiotoxicity (DIC). Our findings revealed that DOX induced pyroptosis through the caspase-1/gasdermin D (GSDMD) and caspase-3/gasdermin E (GSDME) pathways. AS IV treatment significantly improved the cardiac function and alleviated myocardial injury in DOX-exposed mice by regulating intestinal flora and inhibiting pyroptosis; markedly suppressed the levels of cleaved caspase-1, N-GSDMD, cleaved caspase-3, and N-GSDME; and reversed DOX-induced downregulation of silent information regulator 1 (SIRT1) and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mice. The SIRT1 inhibitor EX527 significantly blocked the protective effects of AS IV. Collectively, our results suggest that AS IV protects against DIC by inhibiting pyroptosis through the SIRT1/NLRP3 pathway.
Insights
Astragaloside IV (AS IV) protects against Doxorubicin-induced cardiotoxicity by inhibiting pyroptosis via the SIRT1/NLRP3 pathway. This study reveals AS IV
Area of Science:
- Cardiovascular Pharmacology
- Molecular Toxicology
- Natural Product Chemistry
Background:
- Doxorubicin (DOX) is a vital chemotherapy drug, but its use is limited by cardiotoxicity.
- Astragaloside IV (AS IV), from Astragalus membranaceus, shows cardiovascular benefits, but its mechanism against DOX cardiotoxicity is unknown.
Purpose of the Study:
- To investigate the protective effects of AS IV against Doxorubicin-induced cardiotoxicity (DIC).
- To elucidate the molecular mechanisms underlying AS IV's cardioprotective action, focusing on pyroptosis and the SIRT1/NLRP3 pathway.
Main Methods:
- DOX-induced cardiotoxicity model in mice.
- Assessment of cardiac function and myocardial injury markers.
- Analysis of pyroptosis pathway components (caspase-1, GSDMD, caspase-3, GSDME).
- Evaluation of SIRT1 and NLRP3 inflammasome expression.
- Intervention with SIRT1 inhibitor EX527.
Main Results:
- DOX induced pyroptosis via caspase-1/GSDMD and caspase-3/GSDME pathways.
- AS IV treatment improved cardiac function and reduced myocardial injury in DOX-exposed mice.
- AS IV suppressed cleaved caspase-1, N-GSDMD, cleaved caspase-3, and N-GSDME levels.
- AS IV reversed DOX-induced downregulation of SIRT1 and activation of NLRP3 inflammasome.
- SIRT1 inhibition abolished AS IV's protective effects.
Conclusions:
- AS IV protects against DOX-induced cardiotoxicity by inhibiting pyroptosis.
- The protective mechanism involves the SIRT1/NLRP3 signaling pathway.
- AS IV demonstrates potential as a therapeutic agent to mitigate chemotherapy-induced heart damage.
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