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Adipocyte Enhancer Binding Protein 1 (AEBP1) inhibition mediates cardiac reverse remodeling by regulating MRTFB and RUNX2 signaling [Cut&Run]

ABSTRACT: Persistent activation of cardiac fibroblasts drives excessive extracellular matrix deposition, promoting maladaptive myocardial fibrosis, adverse remodeling and heart failure (HF) progression. Although Adipocyte enhancer binding protein 1 (AEBP1) and Aortic carboxypeptidase-like protein (ACLP, full-length protein coded by AEBP1) have been implicated in pathological fibrosis across multiple organs including the heart, its functional role in cardiac fibrosis remains unknown. Here, we demonstrate that AEBP1 is a critical mediator of myocardial fibrosis and adverse cardiac remodeling. Fibroblast-specific knockout or myocardial knockdown of Aebp1 significantly improves cardiac function and prevents pathological remodeling in murine models of myocardial ischemia and pressure-overload induced injury. In human myocardial tissue culture studies, ACLP overexpression induces pathological remodeling in non-failing hearts, whereas AEBP1 knockdown induces structural reverse remodeling in failing myocardium. Mechanistically, ACLP regulates the expression of MRTFB, RUNX2, SM22 and COL1A1, thereby orchestrating fibroblast activation. Collectively, these findings identify AEBP1 as a central driver of myocardial fibrosis and highlights its inhibition as a promising therapeutic strategy to mitigate both acute and chronic HF.

ORGANISM(S): Mus musculus

PROVIDER: GSE343288 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:Full Title: Transition from Compensated Hypertrophy to Systolic Heart Failure in the Spontaneously Hypertensive Rat: Structure, Function, and Transcript Analysis Gene expression changes and left ventricular remodeling associated with the transition to systolic heart failure (HF) were determined in the spontaneously hypertensive rat (SHR). By combining transcriptomics of left ventricles from six SHR with HF with changes in function and structure we aimed to better understand the molecular events underlying the onset of systolic HF compared to six age-matched, SHR with compensated hypertrophy. Left ventricle (LV) ejection fraction was depressed (82Â±4 to 52Â±3 %) in compensated vs. failing animals.Â Systolic blood pressure decreased and LV end-diastolic and systolic volume increased with HF.Â Failing SHR hearts also demonstrated increases in left and right ventricular mass relative to non-failing SHRs.Â Â LV papillary muscle force development and shortening velocity decreased, Î²-adrenergic responsiveness was depressed, myocardial stiffness and myocardial fibrosis increased with HF relative to non-failing animals. Initial micro-array analysis revealed that 1,431 transcripts were differentially expressed with HF compared to non-failing SHR (p<0.05). Of the identified transcripts, lipopolysaccharide binding protein, the most highly expressed transcript with HF, was negatively correlated to myocardial force while elevated expression of the collagen cross-linking enzyme lysyl oxidase correlated positively with muscle stiffness. Besides these individual transcripts, gene set enrichment analysis (GSEA) identified multiple enriched pathways with HF, most prominent of the altered signaling pathways involved TGF-Î² and insulin signaling. GESA analysis additionally identified altered gene sets involving inflammation, oxidative stress, cell degradation and cell death, among others (all p<0.01). In contrast to diastolic HF where few transcripts are reported to be altered, our data indicate multiple genes and pathways involved in a variety of biological processes characterize the onset of systolic HF, consistent with many functional and structural changes present in the failing hypertensive heart. Comprehensive gene expression profiling of heart failure Rat model vs control.

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Adipocyte Enhancer Binding Protein 1 (AEBP1) inhibition mediates cardiac reverse remodeling by regulating MRTFB and RUNX2 signaling [Cut&Run]

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