Nrf2 deficiency exaggerates doxorubicin-induced cardiotoxicity and cardiac dysfunction

Area of Science:

• Cardiology
• Molecular Biology
• Pharmacology

Background:

• Doxorubicin (Dox) chemotherapy causes cardiotoxicity, limiting its use.
• Oxidative stress and impaired autophagy are implicated in Dox-induced heart damage.
• The precise mechanisms regulating Dox cardiotoxicity remain unclear.

Purpose of the Study:

• To investigate the role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiotoxicity.
• To examine the impact of Nrf2 on myocardial oxidative stress and autophagic activity.
• To elucidate the protective mechanisms of Nrf2 against Dox-induced cardiomyopathy.

Main Methods:

• Used wild-type (WT) and Nrf2 knockout (Nrf2(-/-)) mice treated with Dox.
• Utilized cultured cardiomyocytes with Nrf2 overexpression or knockdown.
• Assessed cardiomyocyte necrosis, cardiac dysfunction, oxidative stress markers, autophagic flux, and protein aggregate accumulation.
• Investigated the effect of autophagy activation (using Atg5) in Nrf2-depleted cells.

Main Results:

• Dox induced cardiotoxicity, oxidative stress, and impaired autophagy in WT mice.
• Nrf2 deficiency exacerbated Dox-induced cardiotoxicity, oxidative stress, and autophagic impairment.
• Nrf2 overexpression protected cardiomyocytes against Dox toxicity by enhancing autophagy and reducing protein aggregates.
• Forced autophagy activation attenuated Dox-induced damage in Nrf2-depleted cardiomyocytes.

Conclusions:

• Nrf2 acts as an endogenous suppressor of Dox-induced cardiotoxicity.
• Nrf2 mitigates Dox cardiotoxicity by regulating both oxidative stress and autophagy.
• Targeting Nrf2 or enhancing autophagy may offer therapeutic strategies against Dox cardiotoxicity.