Abstract Body: Introduction. Myocardial fibrosis is a major determinant of adverse remodeling and heart failure (HF) progression, yet there are no approved anti fibrotic therapies that directly target cardiac fibrosis. Adipocyte enhancer binding protein 1(AEBP1), which encodes full length protein ACLP, has been linked to fibrosis in multiple organs, but its role in cardiac fibrosis in vivo remains undefined.
AEBP1 inhibition prevents fibroblast activation and fibrosis expansion by suppressing pro fibrotic program, ultimately improving cardiac structure and function following myocardial injury.
We generated fibroblast specific Aebp1 knockout (KO) mice, inducing KO at distinct timepoints following myocardial ischemia (MI) and performed longitudinal cardiac functional assessments. We utilized ex vivo human failing/non failing myocardial tissue cultures with AEBP1 knockdown (KD) or ACLP overexpression (OE). To define mechanisms of ACLP mediated fibroblast activation, we performed CUT&RUN for H3K27Ac following ACLP OE to identify active transcriptional networks.
Results. Following acute MI, Aebp1 KO resulted in significant improvements in ejection fraction(EF% by 20%) and fractional shortening(FS% by 15%) compared to untreated WT (n=5/group, 4 weeks post-MI). Aebp1 KO prior to MI, did not lead to cardiac rupture, instead resulted in >20% improvement in EF (n=5/group) and a marked reduction in perisotin positive fibroblasts, indicating diminished pro fibrotic gene transcription. In ex vivo human myocardial tissue culture studies, ACLP OE induced robust pathological remodeling in non failing hearts, whereas AEBP1 KD in failing human myocardium promoted structural reverse remodeling evident from reduced cardiomyocyte hypertrophy and fibrosis. Mechanistically, we also showed that ACLP acts as an upstream regulator of a pro fibrotic transcriptional network, including MRTFB, RUNX2, SM22, and COL1A1, positioning ACLP/AEBP1 as a master orchestrator of fibroblast activation and matrix deposition.
Conclusion. These studies provide the first in vivo evidence that AEBP1 activity is required for fibrosis driven HF progression. Our integrated in vivo, human ex vivo, and mechanistic studies identify AEBP1/ACLP as a druggable molecular hub driving cardiac fibrosis. These findings highlight AEBP1 inhibition as a promising precision anti fibrotic strategy capable of preventing HF progression, promoting reverse remodeling, and addressing a critical unmet clinical need in both acute and chronic HF.