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

Duan Liu; Min Wang; Vishakantha Murthy; Dennis M. McNamara; Thanh Thanh L. Nguyen; Trudy J. Philips; Hridyanshu Vyas; Huanyao Gao; Jyotan Sahni; Randall C. Starling; Leslie T. Cooper; Michelle K. Skime; Anthony Batzler; Gregory D. Jenkins; Simona Barlera; Silvana Pileggi; Luisa Mestroni; Marco Merlo; Gianfranco Sinagra; Florence Pinet; Jan Krejčí; Anna Chaloupka; Jordan D. Miller; Pascal de Groote; Daniel J. Tschumperlin; Richard M. Weinshilboum; Naveen L. Pereira; Karen Janosko; Charles McTiernan; Barry London; Karen Hanley-Yanez; John Gorcsan; Hidekazu Tanaka; Mathew Suffoletto; Cynthia Oblak; Annette McNallan; LuAnne Koenig; Paul Mather; Natalie Pierson; Sharon Rubin; Yanique Bell; Alicia Ervin; John Boehmer; Patricia Frey; Jeffrey Alexis; Janice Schrack; Pam LaDuke; Guillermo Torre-Amione; Jeannie Arredondo; Daniel F. Pauly; Pamela C. Smith; Richard Sheppard; Stephanie Fuoco; Ilan S. Wittstein; Elayne Breton; Vinay Thohan; Deborah Wesley; G. William Dec; Diane Cocca-Spofford; David W. Markham; Lynn Fernandez; Colleen Debes; Mark J. Zucker; Laura Adams; Peter Liu; Judith Renton; Jagat Narula; Byron Allen; Elizabeth Westberg

doi:10.1161/CIRCRESAHA.123.323200

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

Journal article

Peer reviewed

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

Duan Liu, Min Wang, Vishakantha Murthy, Dennis M. McNamara, Thanh Thanh L. Nguyen, Trudy J. Philips, Hridyanshu Vyas, Huanyao Gao, Jyotan Sahni, Randall C. Starling, …

Circulation research, Vol.133(10), pp.810-825

10/27/2023

DOI: 10.1161/CIRCRESAHA.123.323200

PMCID: PMC10746262

PMID: 37800334

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Abstract

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 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 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, 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.

Details

Title: Subtitle: Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis
Creators: Duan Liu - Mayo Clinic
Min Wang - Mayo Clinic
Vishakantha Murthy - Mayo Clinic
Dennis M. McNamara - University of Pittsburgh
Thanh Thanh L. Nguyen - Mayo Clinic
Trudy J. Philips - Mayo Clinic
Hridyanshu Vyas - Mayo Clinic
Huanyao Gao - Mayo Clinic
Jyotan Sahni - Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN. (M.W., V.M., H.V., J.S., N.L.P.)
Randall C. Starling - Cleveland Clinic
Leslie T. Cooper - Mayo Clinic
Michelle K. Skime - Mayo Clinic
Anthony Batzler - Mayo Clinic
Gregory D. Jenkins - Mayo Clinic
Simona Barlera - Mario Negri Institute for Pharmacological Research
Silvana Pileggi - Mario Negri Institute for Pharmacological Research
Luisa Mestroni - University of Colorado Denver
Marco Merlo - Azienda Sanitaria Universitaria Integrata di Trieste
Gianfranco Sinagra - Azienda Sanitaria Universitaria Integrata di Trieste
Florence Pinet - Institut Pasteur de Lille
Jan Krejčí - Masaryk University
Anna Chaloupka - Masaryk University
Jordan D. Miller - Mayo Clinic
Pascal de Groote - Institut Pasteur de Lille
Daniel J. Tschumperlin - Department ofPhysiology and Biomedical Engineering (D.J.T.)
Richard M. Weinshilboum - Mayo Clinic
Naveen L. Pereira - Mayo Clinic
Karen Janosko
Charles McTiernan
Barry London
Karen Hanley-Yanez
John Gorcsan
Hidekazu Tanaka
Mathew Suffoletto
Cynthia Oblak
Annette McNallan
LuAnne Koenig
Paul Mather
Natalie Pierson
Sharon Rubin
Yanique Bell
Alicia Ervin
John Boehmer
Patricia Frey
Jeffrey Alexis
Janice Schrack
Pam LaDuke
Guillermo Torre-Amione
Jeannie Arredondo
Daniel F. Pauly
Pamela C. Smith
Richard Sheppard
Stephanie Fuoco
Ilan S. Wittstein
Elayne Breton
Vinay Thohan
Deborah Wesley
G. William Dec
Diane Cocca-Spofford
David W. Markham
Lynn Fernandez
Colleen Debes
Mark J. Zucker
Laura Adams
Peter Liu
Judith Renton
Jagat Narula
Byron Allen
Elizabeth Westberg
Resource Type: Journal article
Publication Details: Circulation research, Vol.133(10), pp.810-825
DOI: 10.1161/CIRCRESAHA.123.323200
PMID: 37800334
PMCID: PMC10746262
NLM abbreviation: Circ Res
ISSN: 0009-7330
eISSN: 1524-4571
Language: English
Electronic publication date: 10/06/2023
Date published: 10/27/2023
Academic Unit: Molecular Physiology and Biophysics; Pathology; Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984474909902771

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