SESN2-Mediated AKT/GSK-3β/NRF2 Activation to Ameliorate Adriamycin Cardiotoxicity in High-Fat Diet-Induced Obese Mice

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Metabolic Diseases

Background:

• Obesity significantly increases susceptibility to adriamycin (ADR)-induced cardiotoxicity.
• The underlying mechanisms linking obesity and ADR cardiotoxicity, particularly the role of antioxidants, require further investigation.
• Sestrin 2 (SESN2), an antioxidant protein, shows potential in mitigating stress-induced cardiomyopathy.

Purpose of the Study:

• To investigate whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high-fat diet (HFD)-induced obese mice.
• To elucidate the molecular signaling pathways involved in SESN2-mediated protection against cardiotoxicity in obesity.

Main Methods:

• Utilized high-fat diet (HFD) induced obese mouse models.
• Administered adriamycin (ADR) to assess cardiotoxicity.
• Manipulated Sestrin 2 (SESN2) expression (overexpression and knockdown) and NRF2 activity (agonist and inhibitor).
• Analyzed key signaling proteins including AKT, GSK-3β, and NRF2 localization.
• Evaluated cardiac pathological and functional parameters.

Main Results:

• Obesity was associated with decreased SESN2 expression in ADR-exposed hearts.
• HFD-induced obesity predisposed mice to ADR cardiotoxicity, linked to inhibited AKT/GSK-3β phosphorylation and reduced NRF2 nuclear translocation.
• Overexpression of SESN2 blocked ADR-induced cardiotoxicity and oxidative damage in obese mice, an effect dependent on NRF2 activity.
• Sulforaphane, an NRF2 agonist, reversed ADR-induced cardiac abnormalities in obese mice.

Conclusions:

• SESN2 plays a critical role in protecting the heart against ADR-induced oxidative damage in obese individuals.
• The protective mechanism involves SESN2 upregulating NRF2 activity via the AKT/GSK-3β signaling pathway.
• SESN2 represents a promising therapeutic target for mitigating anthracycline-related cardiotoxicity in obesity.