Deficiency of p300/CBP-associated factor exacerbates cardiac remodeling by disrupting CAMKK2 acetylation

Abstract

Cardiac remodeling in response to pathological stress is a key driver of heart failure progression, yet the underlying regulatory mechanisms remain incompletely understood. In this study, we investigate the role of the p300/CBP-associated factor (PCAF) in modulating cardiac hypertrophy and dysfunction. Using a CRISPR/Cas9-generated PCAF knockout (KO) mouse model, we demonstrate that loss of PCAF exacerbates cardiac remodeling following isoproterenol (ISP) infusion and transverse aortic constriction (TAC), as evidenced by worsened hypertrophy, fibrosis, and impaired cardiac function. Transcriptomic profiling of TAC-operated hearts revealed disrupted mitochondrial pathways and altered energy metabolism in the absence of PCAF. Mechanistic studies uncovered that PCAF acetylates calcium/calmodulin-dependent protein kinase kinase2 (CAMKK2), a modification essential for the activation of the AMPK pathway via phosphorylation of AMPKα at Thr172. Pharmacological activation of PCAF with SPV106 ameliorated TAC-induced cardiac remodeling and preserved cardiac function, highlighting the therapeutic potential of targeting this pathway. Together, our findings establish PCAF as a key modulator of the CAMKK2–AMPK signaling axis and underscore its importance in maintaining metabolic and structural homeostasis in the stressed heart. These results offer novel insights into the epigenetic regulation of cardiac remodeling and suggest PCAF as a promising target for therapeutic intervention in heart failure.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.