Exp Mol Med. 2026 Apr 20. doi: 10.1038/s12276-026-01698-z. Online ahead of print.
ABSTRACT
Here we aim to elucidate the role of the p300/CBP-associated factor (PCAF) in pathological cardiac remodeling. Specifically, we explore how PCAF-mediated acetylation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) influences AMPK signaling, thereby regulating cardiac hypertrophy and dysfunction under pathological stress. A genetically engineered PCAF-knockout (KO) mouse model was generated using the CRISPR-Cas9 system to evaluate the effect of PCAF deficiency on cardiac remodeling induced by isoproterenol infusion and transverse aortic constriction (TAC). PCAF deficiency significantly aggravated cardiac enlargement with features of eccentric hypertrophy, as demonstrated by histological analysis and echocardiography. To determine these phenotypes were cardiomyocyte specific, we generated a cardiomyocyte-specific conditional KO model, which also showed a dilated cardiomyopathy-like phenotype similar to that of the global-KO mice. Transcriptomic analysis of TAC-operated hearts from wild-type and KO mice revealed enrichment of pathways related to mitochondrial function and energy homeostasis. Mechanistically, PCAF directly acetylated CAMKK2, promoting its activation and the subsequent phosphorylation of AMP-activated protein kinase α (AMPKα) at Thr172, a critical step in maintaining metabolic balance under stresses. These signaling alterations were also observed in the hearts of PCAF-KO hearts subjected to isoproterenol administration or TAC. Pharmacological activation of PCAF with SPV106 effectively attenuated TAC-induced cardiac remodeling, preserving cardiac structure and function. Collectively, these findings identify PCAF as a pivotal regulator of pathological cardiac remodeling through modulation of the CAMKK2-AMPK signaling axis. Loss of PCAF exacerbates stress-induced cardiac hypertrophy and dysfunction, highlighting its potential as a therapeutic target to preserve cardiac function and counteract stress-induced remodeling.
PMID:42009955 | DOI:10.1038/s12276-026-01698-z