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

Abstract

Pathological cardiac hypertrophy induced by pressure overload is a critical precursor to heart failure, necessitating the identification of novel pathogenesis-specific therapeutic targets. Here, we identify aminoacylase-1 (ACY1), a central enzyme in amino acid metabolism, as a critical cardioprotective molecule. ACY1 expression was significantly downregulated in cardiomyocytes from both a mice transverse aortic constriction (TAC) model and patients with hypertrophic cardiomyopathy. Conversely, cardiac specific overexpression of ACY1 in mice substantially alleviated TAC-induced cardiac hypertrophy, dysfunction, and fibrotic remodeling, whereas its inhibition aggravated these pathological features. In vitro, ACY1 overexpression in neonatal rat cardiomyocytes (NRCMs) significantly suppressed angiotensin II (Ang II)-induced hypertrophy, while its inhibition promoted cardiomyocytes hypertrophy. Mechanistically, integrated transcriptomic and molecular analyses revealed that ACY1 binds directly to β-catenin, thereby inhibiting its phosphorylation at Ser675 and subsequent nuclear translocation. ChIP-qPCR assays confirmed that this cytosolic sequestration of β-catenin prevents TCF4-mediated transcription of the pro-hypertrophic ubiquitin carboxyl-terminal hydrolase L1 (UCHL1). Furthermore, KEGG pathway analysis revealed that ACY1 overexpression influenced genes enriched in oxidative phosphorylation. Functional metabolic assays confirmed that ACY1 preserved mitochondrial integrity under stress, rescuing impairments in oxygen consumption rate, extracellular acidification rate, and mitochondrial membrane potential induced by pressure overload. Importantly, the anti-hypertrophic effects of ACY1 were significantly blunted by pharmacological inhibition of the β-catenin/TCF4 pathway. Our findings establish the ACY1/β-catenin/TCF4/UCHL1 pathway as a fundamental mechanism in disease progression, thereby proposing the enhancement of ACY1 function as a rational and innovative strategy to treat pressure-overload heart failure.