Betulin Protects Against Cardiac Hypertrophy by Improving AMPK/Nrf2-Dependent Mitochondrial Function

Area of Science:

• Cardiovascular Research
• Pharmacology
• Molecular Biology

Background:

• Pathological cardiac hypertrophy (PCH) is a major driver of heart failure and mortality, lacking targeted pharmacotherapy.
• Betulin, a natural pentacyclic triterpene, possesses various pharmacological activities.
• Investigating betulin's therapeutic potential in PCH is crucial for developing new treatments.

Purpose of the Study:

• To investigate the therapeutic potential of betulin in pathological cardiac hypertrophy (PCH).
• To elucidate the underlying molecular mechanisms of betulin's action in PCH.
• To assess betulin's effects on cardiac function, injury, and remodeling.

Main Methods:

• PCH induced in mice using angiotensin II (Ang II) infusion and transverse aortic constriction.
• Betulin administered, followed by echocardiography, histological staining, and molecular analyses.
• RNA sequencing, molecular docking, and molecular dynamics simulations used to explore mechanisms, including interactions with AMPK and Nrf2.

Main Results:

• Betulin significantly ameliorated cardiac hypertrophy, fibrosis (by 65%), and dysfunction (improving EF by 13.8%, FS by 11.6%).
• Betulin activated AMPK phosphorylation, promoted Nrf2 nuclear translocation, and upregulated antioxidant genes, restoring mitochondrial function.
• Molecular simulations predicted and experiments confirmed betulin enhances AMPK/Nrf2 interactions, crucial for its cardioprotective effects.

Conclusions:

• Betulin ameliorates pressure overload-induced PCH and mitochondrial dysfunction.
• Betulin exerts its therapeutic effects by activating the AMPK/Nrf2 signaling pathway.
• Betulin shows promise as a novel therapeutic agent for pathological cardiac hypertrophy.