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Role of CDCP1 and Cardiac Fibrosis in a Mouse Model of Dilated Cardiomyopathy (DCM)

ABSTRACT: Cardiac fibrosis is a common pathological feature of various cardiac diseases that contributes significantly to heart failure progression and poor clinical outcomes. Recent genetic studies have shown that lower expression of CUB domain-containing protein 1 (CDCP1) is linked to myocardial recovery, but its direct role in cardiac pathophysiology remains unkown. In this study, we investigated the functional contribution of CDCP1 to pressure overload-induced cardiac remodeling and fibrosis. CDCP1 deletion attenuated Ang II/PE-induced cardiac dysfunction as demonstrated by reduced left ventricular mass index and improved cardiac function compared to wild-type controls. Histological analysis revealed significantly decreased cardiac fibrosis in CDCP1-KO mice. Transcriptomic profiling revealed that CDCP1 KO attenuates cardiac fibrosis through downregulation of matrix metalloproteases, collagen biosynthesis and limiting the pathological remodeling extracellular matrix. Spatial transcriptomics further revealed region-specific alterations in fibrotic and inflammatory signatures among the subtypes of cardiomyocytes and fibroblasts, suggesting localized CDCP1-dependent effects on cardiac remodeling. Our findings establish CDCP1 as a critical regulator of pressure overload-induced cardiac fibrosis and dysfunction. Our work provides direct evidence supporting CDCP1 inhibition as a potential therapeutic strategy for cardiac fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE303631 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:Chronic pressure overload initiates a series of molecular alterations in the human heart that predate macroscopic organ-level remodeling and downstream heart failure (HF). We hypothesized that integrating easily accessible circulating mediators (proteome) with their expression in the heart (transcriptome) may prioritize targets for study in human pressure overload. Among individuals with severe aortic stenosis (AS)—a pressure overload state—we measured the circulating proteome (Olink) and examined associations with myocardial structure/function (N=519), cardiac MRI-based tissue fibrosis (N=145), and outcomes in AS (N=802). We constructed proteomic signatures of cardiac remodeling and tested their association with HF in the UK Biobank (N=36,668). For proteo-transcriptional integration, we examined a "remodeling proteome” prioritized by proteome-phenotype relations at the transcriptional level via single nuclear RNA-sequencing (snRNA-seq) in 20 human hearts (11 with AS at the time of surgical aortic valve replacement [AVR] and 9 donor hearts not used for transplantation). We identified three principal components of myocardial remodeling (across 12 echocardiographic measures in 503 patients with AS) loaded on cardiac morphology, systolic, and diastolic function traits. Proteins associated with these components (the “remodeling proteome”) specified both known and novel mediators of fibrosis, hypertrophy, and oxidative stress, several of which were associated with interstitial fibrosis by cardiac MRI. Proteomic signatures of remodeling were strongly linked to mortality (AS cohort and UK Biobank) and incident HF (UK Biobank). At a myocardial level, we observed broad differential expression of genes encoding the remodeling proteome between AS and donor hearts, featuring convergent fibrosis pathways (WNT9A, ITGA6, AGRN, CRIM1, SEMA4C, LAYN, PTX3, HMOX1) and metabolic-inflammatory signaling (ENPP2/ATX, TNF), among others. Differential expression of proteo-transcriptionally prioritized genes was prominent in fibroblasts, cardiomyocytes, and endothelial cells. Proteo-transcriptional prioritization in human pressure overload hearts identifies both known and novel targets that are mechanistically relevant to HF pathogenesis. Future integrative studies to index circulating biomarkers over time to myocardial tissue level is warranted to inform pathways of HF progression.

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Role of CDCP1 and Cardiac Fibrosis in a Mouse Model of Dilated Cardiomyopathy (DCM)

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