Cardiac ACY1 ameliorates pathological hypertrophy by suppressing β-catenin/TCF4 signaling

Area of Science:

• Cardiovascular Biology
• Molecular Metabolism
• Heart Failure Pathogenesis

Background:

• Pathological cardiac hypertrophy is a key driver of heart failure following pressure overload.
• Identifying novel therapeutic targets is crucial for treating this condition.
• Aminoacylase-1 (ACY1), an amino acid metabolism enzyme, is investigated for its role in cardiac health.

Purpose of the Study:

• To elucidate the role of Aminoacylase-1 (ACY1) in pressure-overload-induced cardiac hypertrophy.
• To identify the molecular mechanisms underlying ACY1's cardioprotective effects.
• To evaluate ACY1 as a potential therapeutic target for heart failure.

Main Methods:

• Utilized a mouse transverse aortic constriction (TAC) model and in vitro neonatal rat cardiomyocytes (NRCMs).
• Assessed cardiac function, hypertrophy, and fibrosis.
• Performed transcriptomic analysis, co-immunoprecipitation, ChIP-qPCR, and metabolic assays.
• Investigated the interaction between ACY1, β-catenin, TCF4, and UCHL1.

Main Results:

• ACY1 expression was reduced in pressure-overload hypertrophy models.
• Cardiac overexpression of ACY1 alleviated hypertrophy and dysfunction, while inhibition worsened it.
• ACY1 directly binds β-catenin, preventing its nuclear translocation and suppressing TCF4-mediated UCHL1 transcription.
• ACY1 preserved mitochondrial function and oxidative phosphorylation.

Conclusions:

• The ACY1/β-catenin/TCF4/UCHL1 pathway is a critical regulator of cardiac hypertrophy.
• ACY1 exhibits significant cardioprotective effects by maintaining mitochondrial integrity and inhibiting pro-hypertrophic signaling.
• Enhancing ACY1 function represents a promising therapeutic strategy for pressure-overload heart failure.