Dexmedetomidine inhibits ferroptosis through the Akt/GSK3β/Nrf2 axis and alleviates adriamycin-induced cardiotoxicity

Area of Science:

• Cardiology
• Pharmacology
• Molecular Biology

Background:

• Adriamycin (ADR) cardiotoxicity limits its use, with limited effective and safe protective agents.
• Dexrazoxane (DXZ), the current standard, has significant adverse reactions.
• A cardioprotective agent that preserves ADR's anti-tumor effect is needed.

Purpose of the Study:

• To investigate the cardioprotective effects of Dexmedetomidine (DEX) against ADR-induced cardiotoxicity (DIC).
• To elucidate the underlying molecular mechanisms of DEX in mitigating DIC.
• To assess if DEX affects the anti-tumor activity of ADR.

Main Methods:

• Established a rat model of Adriamycin-induced cardiotoxicity (DIC).
• Utilized echocardiography to assess cardiac function (ESV, EDV, EF, FS).
• Performed in vitro experiments measuring protein levels (ANP, BNP, MHC, Collagen III) and ferroptosis markers.
• Investigated the role of the Akt/Gsk3β/Nrf2 signaling axis and ferroptosis using Erastin.

Main Results:

• DEX treatment significantly improved cardiac function and reduced cardiomyocyte hypertrophy and myocardial fibrosis in the DIC model.
• DEX reversed ADR-induced upregulation of cardiac stress markers (ANP, BNP, MHC, Collagen III).
• DEX demonstrated cardioprotection by inhibiting ferroptosis, mediated through the Akt/Gsk3β/Nrf2 pathway, without compromising ADR's anti-tumor effect.

Conclusions:

• Dexmedetomidine (DEX) is a promising therapeutic agent for preventing Adriamycin-induced cardiotoxicity (DIC).
• DEX exerts its protective effects by inhibiting ferroptosis via the Nrf2 pathway.
• DEX offers a potential strategy for improving cancer therapy by protecting the heart without reducing chemotherapy efficacy.