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Article Dans Une Revue Circulation Research Année : 2023

Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis

Duan Liu
Min Wang
Vishakantha Murthy
Dennis Mcnamara
  • Fonction : Auteur
Thanh Thanh L. Nguyen
  • Fonction : Auteur
Trudy Philips
  • Fonction : Auteur
Hridyanshu Vyas
Huanyao Gao
Jyotan Sahni
Randall Starling
Leslie Cooper
Michelle Skime
Anthony Batzler
Gregory Jenkins
  • Fonction : Auteur
Silvana Pileggi
Luisa Mestroni
Marco Merlo
  • Fonction : Auteur
Gianfranco Sinagra
Jan Krejčí
Anna Chaloupka
Jordan Miller
  • Fonction : Auteur
Daniel Tschumperlin
  • Fonction : Auteur
Richard Weinshilboum
  • Fonction : Auteur
Naveen Pereira

Résumé

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5′-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P =7.12×10 −7 ). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.
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Dates et versions

hal-04277545 , version 1 (09-11-2023)

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Citer

Duan Liu, Min Wang, Vishakantha Murthy, Dennis Mcnamara, Thanh Thanh L. Nguyen, et al.. Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis. Circulation Research, 2023, 133 (10), pp.810-825. ⟨10.1161/CIRCRESAHA.123.323200⟩. ⟨hal-04277545⟩
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