Phloretin Prevents Diabetic Cardiomyopathy by Dissociating Keap1/Nrf2 Complex and Inhibiting Oxidative Stress

Area of Science:

• Cardiovascular Research
• Pharmacology
• Molecular Biology

Background:

• Diabetic cardiomyopathy (DCM) is characterized by inflammation and oxidative stress in cardiomyocytes, driven by hyperglycemia.
• Current treatments for DCM often focus on managing blood glucose, but targeting the underlying pathological processes is crucial.
• Phloretin (PHL), a natural product, exhibits known anti-inflammatory, anticancer, and antioxidant properties.

Purpose of the Study:

• To investigate the potential of Phloretin (PHL) in ameliorating high glucose-induced oxidative stress, hypertrophy, and fibrosis in cardiac cells.
• To evaluate PHL's efficacy in attenuating inflammation- and oxidation-mediated cardiac injury in a diabetic mouse model.
• To elucidate the molecular mechanism underlying PHL's protective effects, particularly its interaction with the Keap1/Nrf2 pathway.

Main Methods:

• Utilized high glucose-stimulated H9c2 cardiac cells to assess PHL's effects on inflammatory, oxidative, hypertrophy, and fibrosis markers.
• Administered PHL to diabetic mice to measure serum biomarkers (LDH, AST, CK-MB) and evaluate cardiac fibrosis and oxidative stress.
• Employed molecular modeling and immunoblotting to confirm PHL's interaction with the Keap1/Nrf2 pathway by assessing binding and Nrf2 expression.

Main Results:

• PHL significantly inhibited the expression of pro-inflammatory, pro-oxidant, hypertrophy, and fibrosis cytokines in high glucose-exposed H9c2 cells.
• In diabetic mice, PHL treatment reduced serum levels of LDH, AST, and CK-MB, and attenuated cardiac fibrosis and oxidative stress.
• Molecular modeling and immunoblotting confirmed that PHL directly binds Keap1, obstructing the Nrf2-Keap1 interaction and promoting Nrf2 expression.

Conclusions:

• Phloretin (PHL) demonstrates significant protective effects against high glucose-induced cardiomyocyte oxidative and fibrotic injury.
• PHL's mechanism involves modulating the Keap1/Nrf2 pathway, suggesting its therapeutic potential.
• Targeting the Keap1/Nrf2 pathway with agents like PHL offers a novel therapeutic strategy for diabetic cardiomyopathy (DCM).