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Published on: May 2, 2016
CDCP1 Deletion Protects Against Pressure Overload-Induced Cardiac Dysfunction and Fibrosis in Mice
Naveen Pereira1, Rachad Ghazal1, Akshatha N Srinivas1
1Mayo Clinic.
Insights
Reduced CUB domain-containing protein 1 (CDCP1) expression mitigates cardiac fibrosis and improves heart recovery. This study demonstrates CDCP1
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Fibrosis Research
Background:
- Reduced CUB domain-containing protein 1 (CDCP1) expression is linked to improved myocardial recovery in heart failure patients.
- CDCP1's role in in vivo cardiac fibrosis is not well understood, despite its in vitro effects on cardiac fibroblast proliferation.
Purpose of the Study:
- To investigate the in vivo role of CDCP1 in cardiac fibrotic remodeling and heart failure progression.
Main Methods:
- Utilized a Cdcp1-knockout mouse model subjected to pressure overload (angiotensin II/phenylephrine).
- Performed echocardiography, histologic analysis, gene expression profiling, and spatial transcriptomics.
- Conducted complementary studies involving CDCP1 knockdown in human ventricular fibroblasts.
Main Results:
- Cdcp1 deletion attenuated cardiac fibrosis, reduced left ventricular mass, and decreased pro-fibrotic gene expression.
- Spatial transcriptomics revealed reduced fibroblast activation (FB5) and pro-inflammatory cardiomyocyte populations (CM4) in Cdcp1-knockout hearts.
- CDCP1 knockdown in human fibroblasts decreased extracellular matrix gene expression and collagen I deposition.
Conclusions:
- CDCP1 is a key regulator of cardiac fibrotic remodeling in vivo.
- Targeting CDCP1 may offer a novel therapeutic strategy for heart failure treatment.
Abstract:
Human genomic studies link reduced CUB domain-containing protein 1 (CDCP1) expression with myocardial recovery in heart failure. While CDCP1 regulates cardiac fibroblast proliferation in vitro, it's in vivo role in cardiac fibrosis remains unclear. Using a Cdcp1-knockout (KO) angiotensin II/phenylephrine mouse model, we show that Cdcp1 deletion reduces echocardiographic left ventricular mass, histologic cardiac fibrosis, and pro-fibrotic gene expression, along with decreased fibroblast activation and inflammatory markers. Spatial transcriptomics identified a pressure overload-expanded fibroblast subpopulation enriched for growth factor and TGF-β signaling (FB5), which was markedly attenuated in Cdcp1-KO hearts, alongside reduction of a pro-inflammatory cardiomyocyte subtype (CM4). Complementary studies in human ventricular fibroblasts demonstrate that CDCP1 knockdown reduced extracellular matrix gene expression and collagen I deposition. These findings establish CDCP1 as a regulator of cardiac fibrotic remodeling in vivo and open avenues for its further investigation as a potential therapeutic target.
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